[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2010 Edition]
[From the U.S. Government Printing Office]
[[Page i]]
21
Parts 600 to 799
Revised as of April 1, 2010
Food and Drugs
________________________
Containing a codification of documents of general
applicability and future effect
As of April 1, 2010
With Ancillaries
Published by
Office of the Federal Register
National Archives and Records
Administration
A Special Edition of the Federal Register
[[Page ii]]
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Table of Contents
Page
Explanation................................................. v
Title 21:
Chapter I--Food and Drug Administration, Department
of Health and Human Services (Continued) 3
Finding Aids:
Table of CFR Titles and Chapters........................ 169
Alphabetical List of Agencies Appearing in the CFR...... 189
List of CFR Sections Affected........................... 199
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Cite this Code: CFR
To cite the regulations in
this volume use title,
part and section number.
Thus, 21 CFR 600.2 refers
to title 21, part 600,
section 2.
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[[Page v]]
EXPLANATION
The Code of Federal Regulations is a codification of the general and
permanent rules published in the Federal Register by the Executive
departments and agencies of the Federal Government. The Code is divided
into 50 titles which represent broad areas subject to Federal
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parts covering specific regulatory areas.
Each volume of the Code is revised at least once each calendar year
and issued on a quarterly basis approximately as follows:
Title 1 through Title 16.................................as of January 1
Title 17 through Title 27..................................as of April 1
Title 28 through Title 41...................................as of July 1
Title 42 through Title 50................................as of October 1
The appropriate revision date is printed on the cover of each
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OMB CONTROL NUMBERS
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collection request.
[[Page vi]]
Many agencies have begun publishing numerous OMB control numbers as
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(c) The incorporating document is drafted and submitted for
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CFR INDEXES AND TABULAR GUIDES
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the revision dates of the 50 CFR titles.
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Raymond A. Mosley,
Director,
Office of the Federal Register.
April 1, 2010.
[[Page ix]]
THIS TITLE
Title 21--Food and Drugs is composed of nine volumes. The parts in
these volumes are arranged in the following order: Parts 1-99, 100-169,
170-199, 200-299, 300-499, 500-599, 600-799, 800-1299 and 1300-end. The
first eight volumes, containing parts 1-1299, comprise Chapter I--Food
and Drug Administration, Department of Health and Human Services. The
ninth volume, containing part 1300 to end, includes Chapter II--Drug
Enforcement Administration, Department of Justice, and Chapter III--
Office of National Drug Control Policy. The contents of these volumes
represent all current regulations codified under this title of the CFR
as of April 1, 2010.
For this volume, Bonnie Fritts was Chief Editor. The Code of Federal
Regulations publication program is under the direction of Michael L.
White, assisted by Ann Worley.
[[Page 1]]
TITLE 21--FOOD AND DRUGS
(This book contains parts 600 to 799)
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Part
chapter i--Food and Drug Administration, Department of
Health and Human Services (Continued)..................... 600
[[Page 3]]
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)
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Editorial Note: Nomenclature changes to chapter I appear at 59 FR
14366, Mar. 28, 1994, and 66 FR 56035, Nov. 6, 2001.
SUBCHAPTER F--BIOLOGICS
Part Page
600 Biological products: general................ 5
601 Licensing................................... 21
606 Current good manufacturing practice for
blood and blood components.............. 48
607 Establishment registration and product
listing for manufacturers of human blood
and blood products...................... 61
610 General biological products standards....... 67
630 General requirements for blood, blood
components, and blood derivatives....... 95
640 Additional standards for human blood and
blood products.......................... 96
660 Additional standards for diagnostic
substances for laboratory tests......... 120
680 Additional standards for miscellaneous
products................................ 132
SUBCHAPTER G--COSMETICS
700 General..................................... 136
701 Cosmetic labeling........................... 144
710 Voluntary registration of cosmetic product
establishments.......................... 157
720 Voluntary filing of cosmetic product
ingredient composition statements....... 158
740 Cosmetic product warning statements......... 162
741-799 [Reserved]
[[Page 5]]
SUBCHAPTER F_BIOLOGICS
PART 600_BIOLOGICAL PRODUCTS: GENERAL--Table of Contents
Subpart A_General Provisions
Sec.
600.2 Mailing addresses.
600.3 Definitions.
Subpart B_Establishment Standards
600.10 Personnel.
600.11 Physical establishment, equipment, animals, and care.
600.12 Records.
600.13 Retention samples.
600.14 Reporting of biological product deviations by licenses
manufacturers.
600.15 Temperatures during shipment.
Subpart C_Establishment Inspection
600.20 Inspectors.
600.21 Time of inspection.
600.22 Duties of inspector.
Subpart D_Reporting of Adverse Experiences
600.80 Postmarketing reporting of adverse experiences.
600.81 Distribution reports.
600.90 Waivers.
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 374;
42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A_General Provisions
Sec. 600.2 Mailing addresses.
(a) Licensed biological products regulated by the Center for
Biologics Evaluation and Research (CBER). Unless otherwise stated in
paragraphs (c) or (d) of this section, or as otherwise prescribed by FDA
regulation, all submissions to CBER referenced in parts 600 through 680
of this chapter, as applicable, must be sent to: Document Control Center
(HFM-99), Center for Biologics Evaluation and Research, Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448. Examples of such submissions include: Biologics license
applications (BLAs) and their amendments and supplements, adverse
experience reports, biological product deviation reports, fatality
reports, and other correspondence. Biological products samples must not
be sent to this address but must be sent to the address in paragraph (c)
of this section.
(b) Licensed biological products regulated by the Center for Drug
Evaluation and Research (CDER). Unless otherwise stated in paragraphs
(b)(1), (b)(2), (b)(3), or (c) of this section, or as otherwise
prescribed by FDA regulation, all submissions to CDER referenced in
parts 600, 601, and 610 of this chapter, as applicable, must be sent to:
CDER Therapeutic Biological Products Document Room, Center for Drug
Evaluation and Research, Food and Drug Administration, 12229 Wilkins
Ave., Rockville, MD 20852. Examples of such submissions include: BLAs
and their amendments and supplements, and other correspondence.
(1) Biological Product Deviation Reporting (CDER). All biological
product deviation reports required under Sec. 600.14 must be sent to:
Division of Compliance Risk Management and Surveillance, Office of
Compliance, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.
(2) Postmarketing Adverse Experience Reporting (CDER). All
postmarketing reports required under Sec. 600.80 must be sent to:
Central Document Room, Center for Drug Evaluation and Research, Food and
Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.
(3) Advertising and Promotional Labeling (CDER). All advertising and
promotional labeling supplements required under Sec. 601.12(f) of this
chapter must be sent to: Division of Drug Marketing, Advertising and
Communication, Center for Drug Evaluation and Research, Food and Drug
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.
[[Page 6]]
(c) Samples and Protocols for licensed biological products regulated
by CBER or CDER. (1) Biological product samples and/or protocols, other
than radioactive biological product samples and protocols, required
under Sec. Sec. 600.13, 600.22, 601.15, 610.2, 660.6, 660.36, or 660.46
of this chapter must be sent by courier service to: Sample Custodian
(ATTN: HFM-672), Food and Drug Administration, Center for Biologics
Evaluation and Research, Bldg: NLRC-B, rm. 113, 5516 Nicholson Lane,
Kensington, MD 20895. The protocol(s) may be placed in the box used to
ship the samples to CBER. A cover letter should not be included when
submitting the protocol with the sample unless it contains pertinent
information affecting the release of the lot.
(2) Radioactive biological products required under Sec. 610.2 of
this chapter must be sent by courier service to: Sample Custodian (ATTN:
HFM-672), Food and Drug Administration, Center for Biologics Evaluation
and Research, Nicholson Lane Research Center, c/o Radiation Safety
Office, National Institutes of Health, 21 Wilson Dr., rm. 107, Bethesda,
MD 20892-6780.
(d) Vaccine Adverse Event Reporting System (VAERS). All VAERS
reports as specified in Sec. 600.80(c) must be sent to: Vaccine Adverse
Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-1100.
(e) Address information for submissions to CBER and CDER other than
those listed in parts 600 through 680 of this chapter are included
directly in the applicable regulations.
(f) Obtain updated mailing address information for biological
products regulated by CBER at http://www.fda.gov/cber/pubinquire.htm, or
for biological products regulated by CDER at http://www.fda.gov/cder/
biologics/default.htm.
[70 FR 14981, Mar. 24, 2005, as amended at 74 FR 13114, Mar. 26, 2009]
Sec. 600.3 Definitions.
As used in this subchapter:
(a) Act means the Public Health Service Act (58 Stat. 682), approved
July 1, 1944.
(b) Secretary means the Secretary of Health and Human Services and
any other officer or employee of the Department of Health and Human
Services to whom the authority involved has been delegated.
(c) Commissioner of Food and Drugs means the Commissioner of the
Food and Drug Administration.
(d) Center for Biologics Evaluation and Research means Center for
Biologics Evaluation and Research of the Food and Drug Administration.
(e) State means a State or the District of Columbia, Puerto Rico, or
the Virgin Islands.
(f) Possession includes among other possessions, Puerto Rico and the
Virgin Islands.
(g) Products includes biological products and trivalent organic
arsenicals.
(h) Biological product means any virus, therapeutic serum, toxin,
antitoxin, or analogous product applicable to the prevention, treatment
or cure of diseases or injuries of man:
(1) A virus is interpreted to be a product containing the minute
living cause of an infectious disease and includes but is not limited to
filterable viruses, bacteria, rickettsia, fungi, and protozoa.
(2) A therapeutic serum is a product obtained from blood by removing
the clot or clot components and the blood cells.
(3) A toxin is a product containing a soluble substance poisonous to
laboratory animals or to man in doses of 1 milliliter or less (or
equivalent in weight) of the product, and having the property, following
the injection of non-fatal doses into an animal, of causing to be
produced therein another soluble substance which specifically
neutralizes the poisonous substance and which is demonstrable in the
serum of the animal thus immunized.
(4) An antitoxin is a product containing the soluble substance in
serum or other body fluid of an immunized animal which specifically
neutralizes the toxin against which the animal is immune.
(5) A product is analogous:
(i) To a virus if prepared from or with a virus or agent actually or
potentially infectious, without regard to the degree of virulence or
toxicogenicity of the specific strain used.
[[Page 7]]
(ii) To a therapeutic serum, if composed of whole blood or plasma or
containing some organic constituent or product other than a hormone or
an amino acid, derived from whole blood, plasma, or serum.
(iii) To a toxin or antitoxin, if intended, irrespective of its
source of origin, to be applicable to the prevention, treatment, or cure
of disease or injuries of man through a specific immune process.
(i) Trivalent organic arsenicals means arsphenamine and its
derivatives (or any other trivalent organic arsenic compound) applicable
to the prevention, treatment, or cure of diseases or injuries of man.
(j) A product is deemed applicable to the prevention, treatment, or
cure of diseases or injuries of man irrespective of the mode of
administration or application recommended, including use when intended
through administration or application to a person as an aid in
diagnosis, or in evaluating the degree of susceptibility or immunity
possessed by a person, and including also any other use for purposes of
diagnosis if the diagnostic substance so used is prepared from or with
the aid of a biological product.
(k) Proper name, as applied to a product, means the name designated
in the license for use upon each package of the product.
(l) Dating period means the period beyond which the product cannot
be expected beyond reasonable doubt to yield its specific results.
(m) Expiration date means the calendar month and year, and where
applicable, the day and hour, that the dating period ends.
(n) The word standards means specifications and procedures
applicable to an establishment or to the manufacture or release of
products, which are prescribed in this subchapter or established in the
biologics license application designed to insure the continued safety,
purity, and potency of such products.
(o) The word continued as applied to the safety, purity and potency
of products is interpreted to apply to the dating period.
(p) The word safety means the relative freedom from harmful effect
to persons affected, directly or indirectly, by a product when prudently
administered, taking into consideration the character of the product in
relation to the condition of the recipient at the time.
(q) The word sterility is interpreted to mean freedom from viable
contaminating microorganisms, as determined by the tests prescribed in
Sec. 610.12 of this chapter.
(r) Purity means relative freedom from extraneous matter in the
finished product, whether or not harmful to the recipient or deleterious
to the product. Purity includes but is not limited to relative freedom
from residual moisture or other volatile substances and pyrogenic
substances.
(s) The word potency is interpreted to mean the specific ability or
capacity of the product, as indicated by appropriate laboratory tests or
by adequately controlled clinical data obtained through the
administration of the product in the manner intended, to effect a given
result.
(t) Manufacturer means any legal person or entity engaged in the
manufacture of a product subject to license under the act;
``Manufacturer'' also includes any legal person or entity who is an
applicant for a license where the applicant assumes responsibility for
compliance with the applicable product and establishment standards.
(u) Manufacture means all steps in propagation or manufacture and
preparation of products and includes but is not limited to filling,
testing, labeling, packaging, and storage by the manufacturer.
(v) Location includes all buildings, appurtenances, equipment and
animals used, and personnel engaged by a manufacturer within a
particular area designated by an address adequate for identification.
(w) Establishment has the same meaning as ``facility'' in section
351 of the Public Health Service Act and includes all locations.
(x) Lot means that quantity of uniform material identified by the
manufacturer as having been thoroughly mixed in a single vessel.
(y) A filling refers to a group of final containers identical in all
respects, which have been filled with the same
[[Page 8]]
product from the same bulk lot without any change that will affect the
integrity of the filling assembly.
(z) Process refers to a manufacturing step that is performed on the
product itself which may affect its safety, purity or potency, in
contrast to such manufacturing steps which do not affect intrinsically
the safety, purity or potency of the product.
(aa) Selling agent or distributor means any person engaged in the
unrestricted distribution, other than by sale at retail, of products
subject to license.
(bb) Container (referred to also as ``final container'') is the
immediate unit, bottle, vial, ampule, tube, or other receptacle
containing the product as distributed for sale, barter, or exchange.
(cc) Package means the immediate carton, receptacle, or wrapper,
including all labeling matter therein and thereon, and the contents of
the one or more enclosed containers. If no package, as defined in the
preceding sentence, is used, the container shall be deemed to be the
package.
(dd) Label means any written, printed, or graphic matter on the
container or package or any such matter clearly visible through the
immediate carton, receptacle, or wrapper.
(ee) Radioactive biological product means a biological product which
is labeled with a radionuclide or intended solely to be labeled with a
radionuclide.
(ff) Amendment is the submission of information to a pending license
application or supplement, to revise or modify the application as
originally submitted.
(gg) Supplement is a request to approve a change in an approved
license application.
(hh) Distributed means the biological product has left the control
of the licensed manufacturer.
(ii) Control means having responsibility for maintaining the
continued safety, purity, and potency of the product and for compliance
with applicable product and establishment standards, and for compliance
with current good manufacturing practices.
(jj) Assess the effects of the change, as used in Sec. 601.12 of
this chapter, means to evaluate the effects of a manufacturing change on
the identity, strength, quality, purity, and potency of a product as
these factors may relate to the safety or effectiveness of the product.
(kk) Specification, as used in Sec. 601.12 of this chapter, means
the quality standard (i.e., tests, analytical procedures, and acceptance
criteria) provided in an approved application to confirm the quality of
products, intermediates, raw materials, reagents, components, in-process
materials, container closure systems, and other materials used in the
production of a product. For the purpose of this definition, acceptance
criteria means numerical limits, ranges, or other criteria for the tests
described.
(ll) Complete response letter means a written communication to an
applicant from FDA usually describing all of the deficiencies that the
agency has identified in a biologics license application or supplement
that must be satisfactorily addressed before it can be approved.
(mm) Resubmission means a submission by the biologics license
applicant or supplement applicant of all materials needed to fully
address all deficiencies identified in the complete response letter. A
biologics license application or supplement for which FDA issued a
complete response letter, but which was withdrawn before approval and
later submitted again, is not a resubmission.
[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 31313, July 25, 1975;
55 FR 11014, Mar. 26, 1990; 61 FR 24232, May 14, 1996; 62 FR 39901, July
24, 1997; 64 FR 56449, Oct. 20, 1999; 65 FR 66634, Nov. 7, 2000; 69 FR
18766, Apr. 8, 2004; 70 FR 14982, Mar. 24, 2005; 73 FR 39610, July 10,
2008]
Subpart B_Establishment Standards
Sec. 600.10 Personnel.
(a) [Reserved]
(b) Personnel. Personnel shall have capabilities commensurate with
their assigned functions, a thorough understanding of the manufacturing
operations which they perform, the necessary training and experience
relating to individual products, and adequate information concerning the
application
[[Page 9]]
of the pertinent provisions of this subchapter to their respective
functions. Personnel shall include such professionally trained persons
as are necessary to insure the competent performance of all
manufacturing processes.
(c) Restrictions on personnel--(1) Specific duties. Persons whose
presence can affect adversely the safety and purity of a product shall
be excluded from the room where the manufacture of a product is in
progress.
(2) Sterile operations. Personnel performing sterile operations
shall wear clean or sterilized protective clothing and devices to the
extent necessary to protect the product from contamination.
(3) Pathogenic viruses and spore-forming organisms. Persons working
with viruses pathogenic for man or with spore-forming microorganisms,
and persons engaged in the care of animals or animal quarters, shall be
excluded from areas where other products are manufactured, or such
persons shall change outer clothing, including shoes, or wear protective
covering prior to entering such areas.
(4) Live vaccine work areas. Persons may not enter a live vaccine
processing area after having worked with other infectious agents in any
other laboratory during the same working day. Only persons actually
concerned with propagation of the culture, production of the vaccine,
and unit maintenance, shall be allowed in live vaccine processing areas
when active work is in progress. Casual visitors shall be excluded from
such units at all times and all others having business in such areas
shall be admitted only under supervision. Street clothing, including
shoes, shall be replaced or covered by suitable laboratory clothing
before entering a live vaccine processing unit. Persons caring for
animals used in the manufacture of live vaccines shall be excluded from
other animal quarters and from contact with other animals during the
same working day.
[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997; 68 FR 75119, Dec.
30, 2003]
Sec. 600.11 Physical establishment, equipment, animals, and care.
(a) Work areas. All rooms and work areas where products are
manufactured or stored shall be kept orderly, clean, and free of dirt,
dust, vermin and objects not required for manufacturing. Precautions
shall be taken to avoid clogging and back-siphonage of drainage systems.
Precautions shall be taken to exclude extraneous infectious agents from
manufacturing areas. Work rooms shall be well lighted and ventilated.
The ventilation system shall be arranged so as to prevent the
dissemination of microorganisms from one manufacturing area to another
and to avoid other conditions unfavorable to the safety of the product.
Filling rooms, and other rooms where open, sterile operations are
conducted, shall be adequate to meet manufacturing needs and such rooms
shall be constructed and equipped to permit thorough cleaning and to
keep air-borne contaminants at a minimum. If such rooms are used for
other purposes, they shall be cleaned and prepared prior to use for
sterile operations. Refrigerators, incubators and warm rooms shall be
maintained at temperatures within applicable ranges and shall be free of
extraneous material which might affect the safety of the product.
(b) Equipment. Apparatus for sterilizing equipment and the method of
operation shall be such as to insure the destruction of contaminating
microorganisms. The effectiveness of the sterilization procedure shall
be no less than that achieved by an attained temperature of 121.5[deg] C
maintained for 20 minutes by saturated steam or by an attained
temperature of 170[deg] C maintained for 2 hours with dry heat.
Processing and storage containers, filters, filling apparatus, and other
pieces of apparatus and accessory equipment, including pipes and tubing,
shall be designed and constructed to permit thorough cleaning and, where
possible, inspection for cleanliness. All surfaces that come in contact
with products shall be clean and free of surface solids, leachable
contaminants, and other materials that will hasten the deterioration of
the product or otherwise render it less suitable for the intended use.
For products for which sterility is a
[[Page 10]]
factor, equipment shall be sterile, unless sterility of the product is
assured by subsequent procedures.
(c) Laboratory and bleeding rooms. Rooms used for the processing of
products, including bleeding rooms, shall be effectively fly-proofed and
kept free of flies and vermin. Such rooms shall be so constructed as to
insure freedom from dust, smoke and other deleterious substances and to
permit thorough cleaning and disinfection. Rooms for animal injection
and bleeding, and rooms for smallpox vaccine animals, shall be
disinfected and be provided with the necessary water, electrical and
other services.
(d) Animal quarters and stables. Animal quarters, stables and food
storage areas shall be of appropriate construction, fly-proofed,
adequately lighted and ventilated, and maintained in a clean, vermin-
free and sanitary condition. No manure or refuse shall be stored as to
permit the breeding of flies on the premises, nor shall the
establishment be located in close proximity to off-property manure or
refuse storage capable of engendering fly breeding.
(e) Restrictions on building and equipment use--(1) Work of a
diagnostic nature. Laboratory procedures of a clinical diagnostic nature
involving materials that may be contaminated, shall not be performed in
space used for the manufacture of products except that manufacturing
space which is used only occasionally may be used for diagnostic work
provided spore-forming pathogenic microorganisms are not involved and
provided the space is thoroughly cleaned and disinfected before the
manufacture of products is resumed.
(2) Spore-forming organisms for supplemental sterilization procedure
control test. Spore-forming organisms used as an additional control in
sterilization procedures may be introduced into areas used for the
manufacture of products, only for the purposes of the test and only
immediately before use for such purposes: Provided, That (i) the
organism is not pathogenic for man or animals and does not produce
pyrogens or toxins, (ii) the culture is demonstrated to be pure, (iii)
transfer of test cultures to culture media shall be limited to the
sterility test area or areas designated for work with spore-forming
organisms, (iv) each culture be labeled with the name of the
microorganism and the statement ``Caution: microbial spores. See
directions for storage, use and disposition.'', and (v) the container of
each culture is designed to withstand handling without breaking.
(3) Work with spore-forming microorganisms. (i) Manufacturing
processes using spore-forming microorganisms conducted in a multiproduct
manufacturing site must be performed under appropriate controls to
prevent contamination of other products and areas within the site.
Prevention of spore contamination can be achieved by using a separate
dedicated building or by using process containment if manufacturing is
conducted in a multiproduct manufacturing building. All product and
personnel movement between the area where the spore-forming
microorganisms are manufactured and other manufacturing areas must be
conducted under conditions that will prevent the introduction of spores
into other areas of the facility.
(ii) If process containment is employed in a multiproduct
manufacturing area, procedures must be in place to demonstrate adequate
removal of the spore-forming microorganism(s) from the manufacturing
area for subsequent manufacture of other products. These procedures must
provide for adequate removal or decontamination of the spore-forming
microorganisms on and within manufacturing equipment, facilities, and
ancillary room items as well as the removal of disposable or product
dedicated items from the manufacturing area. Environmental monitoring
specific for the spore-forming microorganism(s) must be conducted in
adjacent areas during manufacturing operations and in the manufacturing
area after completion of cleaning and decontamination.
(4) Live vaccine processing. Live vaccine processing must be
performed under appropriate controls to prevent cross contamination of
other products and other manufacturing areas within the building.
Appropriate controls must include, at a minimum:
(i)(A) Using a dedicated manufacturing area that is either in a
separate
[[Page 11]]
building, in a separate wing of a building, or in quarters at the blind
end of a corridor and includes adequate space and equipment for all
processing steps up to, but not including, filling into final
containers; and
(B) Not conducting test procedures that potentially involve the
presence of microorganisms other than the vaccine strains or the use of
tissue culture cell lines other than primary cultures in space used for
processing live vaccine; or
(ii) If manufacturing is conducted in a multiproduct manufacturing
building or area, using procedural controls, and where necessary,
process containment. Process containment is deemed to be necessary
unless procedural controls are sufficient to prevent cross contamination
of other products and other manufacturing areas within the building.
Process containment is a system designed to mechanically isolate
equipment or an area that involves manufacturing using live vaccine
organisms. All product, equipment, and personnel movement between
distinct live vaccine processing areas and between live vaccine
processing areas and other manufacturing areas, up to, but not
including, filling in final containers, must be conducted under
conditions that will prevent cross contamination of other products and
manufacturing areas within the building, including the introduction of
live vaccine organisms into other areas. In addition, written procedures
and effective processes must be in place to adequately remove or
decontaminate live vaccine organisms from the manufacturing area and
equipment for subsequent manufacture of other products. Written
procedures must be in place for verification that processes to remove or
decontaminate live vaccine organisms have been followed.
(5) Equipment and supplies--contamination. Equipment and supplies
used in work on or otherwise exposed to any pathogenic or potentially
pathogenic agent shall be kept separated from equipment and supplies
used in the manufacture of products to the extent necessary to prevent
cross-contamination.
(f) Animals used in manufacture--(1) Care of animals used in
manufacturing. Caretakers and attendants for animals used for the
manufacture of products shall be sufficient in number and have adequate
experience to insure adequate care. Animal quarters and cages shall be
kept in sanitary condition. Animals on production shall be inspected
daily to observe response to production procedures. Animals that become
ill for reasons not related to production shall be isolated from other
animals and shall not be used for production until recovery is complete.
Competent veterinary care shall be provided as needed.
(2) Quarantine of animals--(i) General. No animal shall be used in
processing unless kept under competent daily inspection and preliminary
quarantine for a period of at least 7 days before use, or as otherwise
provided in this subchapter. Only healthy animals free from detectable
communicable diseases shall be used. Animals must remain in overt good
health throughout the quarantine periods and particular care shall be
taken during the quarantine periods to reject animals of the equine
genus which may be infected with glanders and animals which may be
infected with tuberculosis.
(ii) Quarantine of monkeys. In addition to observing the pertinent
general quarantine requirements, monkeys used as a source of tissue in
the manufacture of vaccine shall be maintained in quarantine for at
least 6 weeks prior to use, except when otherwise provided in this part.
Only monkeys that have reacted negatively to tuberculin at the start of
the quarantine period and again within 2 weeks prior to use shall be
used in the manufacture of vaccine. Due precaution shall be taken to
prevent cross-infection from any infected or potentially infected
monkeys on the premises. Monkeys to be used in the manufacture of a live
vaccine shall be maintained throughout the quarantine period in cages
closed on all sides with solid materials except the front which shall be
screened, with no more than two monkeys housed in one cage. Cage mates
shall not be interchanged.
(3) Immunization against tetanus. Horses and other animals
susceptible
[[Page 12]]
to tetanus, that are used in the processing steps of the manufacture of
biological products, shall be treated adequately to maintain immunity to
tetanus.
(4) Immunization and bleeding of animals used as a source of
products. Toxins or other nonviable antigens administered in the
immunization of animals used in the manufacture of products shall be
sterile. Viable antigens, when so used, shall be free of contaminants,
as determined by appropriate tests prior to use. Injections shall not be
made into horses within 6 inches of bleeding site. Horses shall not be
bled for manufacturing purposes while showing persistent general
reaction or local reaction near the site of bleeding. Blood shall not be
used if it was drawn within 5 days of injecting the animals with viable
microorganisms. Animals shall not be bled for manufacturing purposes
when they have an intercurrent disease. Blood intended for use as a
source of a biological product shall be collected in clean, sterile
vessels. When the product is intended for use by injection, such vessels
shall also be pyrogen-free.
(5) [Reserved]
(6) Reporting of certain diseases. In cases of actual or suspected
infection with foot and mouth disease, glanders, tetanus, anthrax, gas
gangrene, equine infectious anemia; equine encephalomyelitis, or any of
the pock diseases among animals intended for use or used in the
manufacture of products, the manufacturer shall immediately notify the
Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research (see mailing addresses in Sec.
600.2).
(7) Monkeys used previously for experimental or test purposes.
Monkeys that have been used previously for experimental or test purposes
with live microbiological agents shall not be used as a source of kidney
tissue for the manufacture of vaccine. Except as provided otherwise in
this subchapter, monkeys that have been used previously for other
experimental or test purposes may be used as a source of kidney tissue
upon their return to a normal condition, provided all quarantine
requirements have been met.
(8) Necropsy examination of monkeys. Each monkey used in the
manufacture of vaccine shall be examined at necropsy under the direction
of a qualified pathologist, physician, or veterinarian having experience
with diseases of monkeys, for evidence of ill health, particularly for
(i) evidence of tuberculosis, (ii) presence of herpes-like lesions,
including eruptions or plaques on or around the lips, in the buccal
cavity or on the gums, and (iii) signs of conjunctivitis. If there are
any such signs or other significant gross pathological lesions, the
tissue shall not be used in the manufacture of vaccine.
(g) Filling procedures. Filling procedures shall be such as will not
affect adversely the safety, purity or potency of the product.
(h) Containers and closures. All final containers and closures shall
be made of material that will not hasten the deterioration of the
product or otherwise render it less suitable for the intended use. All
final containers and closures shall be clean and free of surface solids,
leachable contaminants and other materials that will hasten the
deterioration of the product or otherwise render it less suitable for
the intended use. After filling, sealing shall be performed in a manner
that will maintain the integrity of the product during the dating
period. In addition, final containers and closures for products intended
for use by injection shall be sterile and free from pyrogens. Except as
otherwise provided in the regulations of this subchapter, final
containers for products intended for use by injection shall be colorless
and sufficiently transparent to permit visual examination of the
contents under normal light. As soon as possible after filling final
containers shall be labeled as prescribed in Sec. 610.60 et seq. of
this chapter, except that final containers may be stored without such
prescribed labeling provided they are stored in a sealed receptacle
labeled both inside and outside with at least the name of the product,
the lot number, and the filling identification.
[38 FR 32048, Nov. 20, 1973, as amended at 41 FR 10428, Mar. 11, 1976;
49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 68 FR 75119, Dec.
30, 2003; 70 FR 14982, Mar. 24, 2005; 72 FR 59003, Oct. 18, 2007]
[[Page 13]]
Sec. 600.12 Records.
(a) Maintenance of records. Records shall be made, concurrently with
the performance, of each step in the manufacture and distribution of
products, in such a manner that at any time successive steps in the
manufacture and distribution of any lot may be traced by an inspector.
Such records shall be legible and indelible, shall identify the person
immediately responsible, shall include dates of the various steps, and
be as detailed as necessary for clear understanding of each step by one
experienced in the manufacture of products.
(b) Records retention--(1) General. Records shall be retained for
such interval beyond the expiration date as is necessary for the
individual product, to permit the return of any clinical report of
unfavorable reactions. The retention period shall be no less than five
years after the records of manufacture have been completed or six months
after the latest expiration date for the individual product, whichever
represents a later date.
(2) Records of recall. Complete records shall be maintained
pertaining to the recall from distribution of any product upon
notification by the Director, Center for Biologics Evaluation and
Research or the Director, Center for Drug Evaluation and Research, to
recall for failure to conform with the standards prescribed in the
regulations of this subchapter, because of deterioration of the product
or for any other factor by reason of which the distribution of the
product would constitute a danger to health.
(3) Suspension of requirement for retention. The Director, Center
for Biologics Evaluation and Research or the Director, Center for Drug
Evaluation and Research, may authorize the suspension of the requirement
to retain records of a specific manufacturing step upon a showing that
such records no longer have significance for the purposes for which they
were made: Provided, That a summary of such records shall be retained.
(c) Records of sterilization of equipment and supplies. Records
relating to the mode of sterilization, date, duration, temperature and
other conditions relating to each sterilization of equipment and
supplies used in the processing of products shall be made by means of
automatic recording devices or by means of a system of recording which
gives equivalent assurance of the accuracy and reliability of the
record. Such records shall be maintained in a manner that permits an
identification of the product with the particular manufacturing process
to which the sterilization relates.
(d) Animal necropsy records. A necropsy record shall be kept on each
animal from which a biological product has been obtained and which dies
or is sacrificed while being so used.
(e) Records in case of divided manufacturing responsibility. If two
or more establishments participate in the manufacture of a product, the
records of each such establishment must show plainly the degree of its
responsibility. In addition, each participating manufacturer shall
furnish to the manufacturer who prepares the product in final form for
sale, barter or exchange, a copy of all records relating to the
manufacturing operations performed by such participating manufacturer
insofar as they concern the safety, purity and potency of the lots of
the product involved, and the manufacturer who prepares the product in
final form shall retain a complete record of all the manufacturing
operations relating to the product.
[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990; 70 FR 14982, Mar. 24, 2005]
Sec. 600.13 Retention samples.
Manufacturers shall retain for a period of at least 6 months after
the expiration date, unless a different time period is specified in
additional standards, a quantity of representative material of each lot
of each product, sufficient for examination and testing for safety and
potency, except Whole Blood, Cryoprecipitated AHF, Platelets, Red Blood
Cells, Plasma, and Source Plasma and Allergenic Products prepared to a
physician's prescription. Samples so retained shall be selected at
random from either final container material, or from bulk and final
containers, provided they include at least one final container as a
final package, or package-equivalent of such filling of each lot of the
product as intended for
[[Page 14]]
distribution. Such sample material shall be stored at temperatures and
under conditions which will maintain the identity and integrity of the
product. Samples retained as required in this section shall be in
addition to samples of specific products required to be submitted to the
Center for Biologics Evaluation and Research or the Center for Drug
Evaluation and Research (see mailing addresses in Sec. 600.2).
Exceptions may be authorized by the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research, when the lot yields relatively few final containers and when
such lots are prepared by the same method in large number and in close
succession.
[41 FR 10428, Mar. 11, 1976, as amended at 49 FR 23833, June 8, 1984; 50
FR 4133, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14982, Mar.
24, 2005]
Sec. 600.14 Reporting of biological product deviations by licensed
manufacturers.
(a) Who must report under this section? (1) You, the manufacturer
who holds the biological product license and who had control over the
product when the deviation occurred, must report under this section. If
you arrange for another person to perform a manufacturing, holding, or
distribution step, while the product is in your control, that step is
performed under your control. You must establish, maintain, and follow a
procedure for receiving information from that person on all deviations,
complaints, and adverse events concerning the affected product.
(2) Exceptions:
(i) Persons who manufacture only in vitro diagnostic products that
are not subject to licensing under section 351 of the Public Health
Service Act do not report biological product deviations for those
products under this section but must report in accordance with part 803
of this chapter;
(ii) Persons who manufacture blood and blood components, including
licensed manufacturers, unlicensed registered blood establishments, and
transfusion services, do not report biological product deviations for
those products under this section but must report under Sec. 606.171 of
this chapter;
(iii) Persons who manufacture Source Plasma or any other blood
component and use that Source Plasma or any other blood component in the
further manufacture of another licensed biological product must report:
(A) Under Sec. 606.171 of this chapter, if a biological product
deviation occurs during the manufacture of that Source Plasma or any
other blood component; or
(B) Under this section, if a biological product deviation occurs
after the manufacture of that Source Plasma or any other blood
component, and during manufacture of the licensed biological product.
(b) What do I report under this section? You must report any event,
and information relevant to the event, associated with the
manufacturing, to include testing, processing, packing, labeling, or
storage, or with the holding or distribution, of a licensed biological
product, if that event meets all the following criteria:
(1) Either:
(i) Represents a deviation from current good manufacturing practice,
applicable regulations, applicable standards, or established
specifications that may affect the safety, purity, or potency of that
product; or
(ii) Represents an unexpected or unforeseeable event that may affect
the safety, purity, or potency of that product; and
(2) Occurs in your facility or another facility under contract with
you; and
(3) Involves a distributed biological product.
(c) When do I report under this section? You should report a
biological product deviation as soon as possible but you must report at
a date not to exceed 45-calendar days from the date you, your agent, or
another person who performs a manufacturing, holding, or distribution
step under your control, acquire information reasonably suggesting that
a reportable event has occurred.
(d) How do I report under this section You must report on Form FDA-
3486.
(e) Where do I report under this section? (1) For biological
products regulated by the Center for Biologics Evaluation and Research
(CBER), send the completed Form FDA-3486 to the Director, Office of
Compliance and Biologics
[[Page 15]]
Quality (HFM-600) (see mailing addresses in Sec. 600.2), or an
electronic filing through CBER's Web site at http://www.fda.gov/cber/
biodev/biodev.htm.
(2) For biological products regulated by the Center for Drug
Evaluation and Research (CDER), send the completed Form FDA-3486 to the
Division of Compliance Risk Management and Surveillance (HFD-330) (see
mailing addresses in Sec. 600.2). CDER does not currently accept
electronic filings.
(3) If you make a paper filing, you should identify on the envelope
that a biological product deviation report (BPDR) is enclosed.
(f) How does this regulation affect other FDA regulations? This part
supplements and does not supersede other provisions of the regulations
in this chapter. All biological product deviations, whether or not they
are required to be reported under this section, should be investigated
in accordance with the applicable provisions of parts 211 and 820 of
this chapter.
[65 FR 66634, Nov. 7, 2000, as amended at 70 FR 14982, Mar. 24, 2005]
Sec. 600.15 Temperatures during shipment.
The following products shall be maintained during shipment at the
specified temperatures:
(a) Products.
------------------------------------------------------------------------
Product Temperature
------------------------------------------------------------------------
Cryoprecipitated AHF................... -18 [deg]C or colder.
Measles and Rubella Virus Vaccine Live. 10 [deg]C or colder.
Measles Live and Smallpox Vaccine...... Do.
Measles, Mumps, and Rubella Virus Do.
Vaccine Live.
Measles and Mumps Virus Vaccine Live... Do.
Measles Virus Vaccine Live............. Do.
Mumps Virus Vaccine Live............... Do.
Fresh Frozen Plasma.................... -18 [deg]C or colder.
Liquid Plasma.......................... 1 to 10 [deg]C.
Plasma................................. -18 [deg]C or colder.
Platelet Rich Plasma................... Between 1 and 10 [deg]C if the
label indicates storage
between 1 and 6 [deg]C, or all
reasonable methods to maintain
the temperature as close as
possible to a range between 20
and 24 [deg]C, if the label
indicates storage between 20
and 24 [deg]C.
Platelets.............................. Between 1 and 10 [deg]C if the
label indicates storage
between 1 and 6 [deg]C, or all
reasonable methods to maintain
the temperature as close as
possible to a range between 20
to 24 [deg]C, if the label
indicates storage between 20
and 24 [deg]C.
Poliovirus Vaccine Live Oral Trivalent. 0 [deg]C or colder.
Poliovirus Vaccine Live Oral Type I.... Do.
Poliovirus Vaccine Live Oral Type II... Do.
Poliovirus Vaccine Live Oral Type III.. Do.
Red Blood Cells (liquid product)....... Between 1 and 10 [deg]C.
Red Blood Cells Frozen................. -65 [deg]C or colder.
Rubella and Mumps Virus Vaccine Live... 10 [deg]C or colder.
Rubella Virus Vaccine Live............. Do.
Smallpox Vaccine (Liquid Product)...... 0 [deg]C or colder.
Source Plasma.......................... -5 [deg]C or colder.
Source Plasma Liquid................... 10 [deg]C or colder.
Whole Blood............................ Blood that is transported from
the collecting facility to the
processing facility shall be
transported in an environment
capable of continuously
cooling the blood toward a
temperature range of 1 to 10
[deg]C, or at a temperature as
close as possible to 20 to 24
[deg]C for a period not to
exceed 6 hours. Blood
transported from the storage
facility shall be placed in an
appropriate environment to
maintain a temperature range
between 1 to 10 [deg]C during
shipment.
Yellow Fever Vaccine................... 0 [deg]C or colder.
------------------------------------------------------------------------
(b) Exemptions. Exemptions or modifications shall be made only upon
written approval, in the form of a supplement to the biologics license
application, approved by the Director, Center for Biologics Evaluation
and Research.
[39 FR 39872, Nov. 12, 1974, as amended at 49 FR 23833, June 8, 1984; 50
FR 4133, Jan. 29, 1985; 50 FR 9000, Mar. 6, 1985; 55 FR 11013, Mar. 26,
1990; 59 FR 49351, Sept. 28, 1994; 64 FR 56449, Oct. 20, 1999]
[[Page 16]]
Subpart C_Establishment Inspection
Sec. 600.20 Inspectors.
Inspections shall be made by an officer of the Food and Drug
Administration having special knowledge of the methods used in the
manufacture and control of products and designated for such purposes by
the Commissioner of Food and Drugs, or by any officer, agent, or
employee of the Department of Health and Human Services specifically
designated for such purpose by the Secretary.
[38 FR 32048, Nov. 20, 1973]
Sec. 600.21 Time of inspection.
The inspection of an establishment for which a biologics license
application is pending need not be made until the establishment is in
operation and is manufacturing the complete product for which a
biologics license is desired. In case the license is denied following
inspection for the original license, no reinspection need be made until
assurance has been received that the faulty conditions which were the
basis of the denial have been corrected. An inspection of each licensed
establishment and its additional location(s) shall be made at least once
every 2 years. Inspections may be made with or without notice, and shall
be made during regular business hours unless otherwise directed.
[38 FR 32048, Nov. 20, 1973, as amended at 48 FR 26314, June 7, 1983; 64
FR 56449, Oct. 20, 1999]
Sec. 600.22 Duties of inspector.
The inspector shall:
(a) Call upon the active head of the establishment, stating the
object of his visit,
(b) Interrogate the proprietor or other personnel of the
establishment as he may deem necessary,
(c) Examine the details of location, construction, equipment and
maintenance, including stables, barns, warehouses, manufacturing
laboratories, bleeding clinics maintained for the collection of human
blood, shipping rooms, record rooms, and any other structure or
appliance used in any part of the manufacture of a product,
(d) Investigate as fully as he deems necessary the methods of
propagation, processing, testing, storing, dispensing, recording, or
other details of manufacture and distribution of each licensed product,
or product for which a license has been requested, including observation
of these procedures in actual operation,
(e) Obtain and cause to be sent to the Director, Center for
Biologics Evaluation and Research or the Director, Center for Drug
Evaluation and Research (see mailing addresses in Sec. 600.2), adequate
samples for the examination of any product or ingredient used in its
manufacture,
(f) Bring to the attention of the manufacturer any fault observed in
the course of inspection in location, construction, manufacturing
methods, or administration of a licensed establishment which might lead
to impairment of a product,
(g) Inspect and copy, as circumstances may require, any records
required to be kept pursuant to Sec. 600.12,
(h) Certify as to the condition of the establishment and of the
manufacturing methods followed and make recommendations as to action
deemed appropriate with respect to any application for license or any
license previously issued.
[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990; 70 FR 14982, Mar. 24, 2005]
Subpart D_Reporting of Adverse Experiences
Source: 59 FR 54042, Oct. 27, 1994, unless otherwise noted.
Sec. 600.80 Postmarketing reporting of adverse experiences.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse experience. Any adverse event associated with the use of a
biological product in humans, whether or not considered product related,
including the following: An adverse event occurring in the course of the
use of a biological product in professional practice; an adverse event
occurring from overdose of the product whether accidental or
intentional; an adverse event occurring from abuse of the product; an
[[Page 17]]
adverse event occurring from withdrawal of the product; and any failure
of expected pharmacological action.
Blood Component. As defined in Sec. 606.3(c) of this chapter.
Disability. A substantial disruption of a person's ability to
conduct normal life functions.
Life-threatening adverse experience. Any adverse experience that
places the patient, in the view of the initial reporter, at immediate
risk of death from the adverse experience as it occurred, i.e., it does
not include an adverse experience that, had it occurred in a more severe
form, might have caused death.
Serious adverse experience. Any adverse experience occurring at any
dose that results in any of the following outcomes: Death, a life-
threatening adverse experience, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious adverse experience
when, based upon appropriate medical judgment, they may jeopardize the
patient or subject and may require medical or surgical intervention to
prevent one of the outcomes listed in this definition. Examples of such
medical events include allergic bronchospasm requiring intensive
treatment in an emergency room or at home, blood dyscrasias or
convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse.
Unexpected adverse experience: Any adverse experience that is not
listed in the current labeling for the biological product. This includes
events that may be symptomatically and pathophysiologically related to
an event listed in the labeling, but differ from the event because of
greater severity or specificity. For example, under this definition,
hepatic necrosis would be unexpected (by virtue of greater severity) if
the labeling only referred to elevated hepatic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral vasculitis would be
unexpected (by virtue of greater specificity) if the labeling only
listed cerebral vascular accidents. ``Unexpected,'' as used in this
definition, refers to an adverse experience that has not been previously
observed (i.e., included in the labeling) rather than from the
perspective of such experience not being anticipated from the
pharmacological properties of the pharmaceutical product.
(b) Review of adverse experiences. Any person having a biologics
license under Sec. 601.20 of this chapter shall promptly review all
adverse experience information pertaining to its product obtained or
otherwise received by the licensed manufacturer from any source, foreign
or domestic, including information derived from commercial marketing
experience, postmarketing clinical investigations, postmarketing
epidemiological/surveillance studies, reports in the scientific
literature, and unpublished scientific papers. Licensed manufacturers
are not required to resubmit to FDA adverse product experience reports
forwarded to the licensed manufacturer by FDA; licensed manufacturers,
however, must submit all followup information on such reports to FDA.
Any person subject to the reporting requirements under paragraph (c) of
this section shall also develop written procedures for the surveillance,
receipt, evaluation, and reporting of postmarketing adverse experiences
to FDA.
(c) Reporting requirements. The licensed manufacturer shall report
to FDA adverse experience information, as described in this section. The
licensed manufacturer shall submit two copies of each report described
in this section for nonvaccine biological products to the Center for
Biologics Evaluation and Research (HFM-210), or to the Center for Drug
Evaluation and Research (see mailing addresses in Sec. 600.2). Submit
all vaccine adverse experience reports to: Vaccine Adverse Event
Reporting System (VAERS) (see mailing addresses in Sec. 600.2). FDA may
waive the requirement for the second copy in appropriate instances.
(1)(i) Postmarketing 15-day ``Alert reports''. The licensed
manufacturer shall report each adverse experience that is both serious
and unexpected, whether foreign or domestic, as soon as possible but in
no case later than 15 calendar
[[Page 18]]
days of initial receipt of the information by the licensed manufacturer.
(ii) Postmarketing 15-day ``Alert reports''--followup. The licensed
manufacturer shall promptly investigate all adverse experiences that are
the subject of these postmarketing 15-day Alert reports and shall submit
followup reports within 15 calendar days of receipt of new information
or as requested by FDA. If additional information is not obtainable,
records should be maintained of the unsuccessful steps taken to seek
additional information. Postmarketing 15-day Alert reports and followups
to them shall be submitted under separate cover.
(iii) Submission of reports. The requirements of paragraphs
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of
postmarketing 15-day Alert reports, shall also apply to any person whose
name appears on the label of a licensed biological product as a
manufacturer, packer, distributor, shared manufacturer, joint
manufacturer, or any other participant involved in divided
manufacturing. To avoid unnecessary duplication in the submission to FDA
of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this
section, obligations of persons other than the licensed manufacturer of
the final biological product may be met by submission of all reports of
serious adverse experiences to the licensed manufacturer of the final
product. If a person elects to submit adverse experience reports to the
licensed manufacturer of the final product rather than to FDA, the
person shall submit each report to the licensed manufacturer of the
final product within 5 calendar days of receipt of the report by the
person, and the licensed manufacturer of the final product shall then
comply with the requirements of this section. Under this circumstance, a
person who elects to submit reports to the licensed manufacturer of the
final product shall maintain a record of this action which shall
include:
(A) A copy of all adverse biological product experience reports
submitted to the licensed manufacturer of the final product;
(B) The date the report was received by the person;
(C) The date the report was submitted to the licensed manufacturer
of the final product; and-
(D) The name and address of the licensed manufacturer of the final
product.
(iv) Report identification. Each report submitted under this
paragraph shall bear prominent identification as to its contents, i.e.,
``15-day Alert report,'' or ``15-day Alert report-followup.''
(2) Periodic adverse experience reports. (i) The licensed
manufacturer shall report each adverse experience not reported under
paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years
from the date of issuance of the biologics license, and then at annual
intervals. The licensed manufacturer shall submit each quarterly report
within 30 days of the close of the quarter (the first quarter beginning
on the date of issuance of the biologics license) and each annual report
within 60 days of the anniversary date of the issuance of the biologics
license. Upon written notice, FDA may extend or reestablish the
requirement that a licensed manufacturer submit quarterly reports, or
require that the licensed manufacturer submit reports under this section
at different times than those stated. Followup information to adverse
experiences submitted in a periodic report may be submitted in the next
periodic report.
(ii) Each periodic report shall contain:
(A) A narrative summary and analysis of the information in the
report and an analysis of the 15-day Alert reports submitted during the
reporting interval (all 15-day Alert reports being appropriately
referenced by the licensed manufacturer's patient identification number,
adverse reaction term(s), and date of submission to FDA);
(B) A form designated for Adverse Experience Reporting by FDA for
each adverse experience not reported under paragraph (c)(1)(i) of this
section (with an index consisting of a line listing of the licensed
manufacturer's patient identification number and adverse reaction
term(s)); and
[[Page 19]]
(C) A history of actions taken since the last report because of
adverse experiences (for example, labeling changes or studies
initiated).
(iii) Periodic reporting, except for information regarding 15-day
Alert reports, does not apply to adverse experience information obtained
from postmarketing studies (whether or not conducted under an
investigational new drug application), from reports in the scientific
literature, and from foreign marketing experience.
(d) Scientific literature. (1) A 15-day Alert report based on
information from the scientific literature shall be accompanied by a
copy of the published article. The 15-day Alert reporting requirements
in paragraph (c)(1)(i) of this section (i.e., serious, unexpected
adverse experiences) apply only to reports found in scientific and
medical journals either as case reports or as the result of a formal
clinical trial.
(2) As with all reports submitted under paragraph (c)(1)(i) of this
section, reports based on the scientific literature shall be submitted
on the reporting form designated by FDA or comparable format as
prescribed by paragraph (f) of this section. In cases where the licensed
manufacturer believes that preparing the form designated by FDA
constitutes an undue hardship, the licensed manufacturer may arrange
with the Division of Biostatistics and Epidemiology (HFM-210) for an
acceptable alternative reporting format.
(e) Postmarketing studies. (1) Licensed manufacturers are not
required to submit a 15-day Alert report under paragraph (c) of this
section for an adverse experience obtained from a postmarketing clinical
study (whether or not conducted under a biological investigational new
drug application) unless the licensed manufacturer concludes that there
is a reasonable possibility that the product caused the adverse
experience.
(2) The licensed manufacturer shall separate and clearly mark
reports of adverse experiences that occur during a postmarketing study
as being distinct from those experiences that are being reported
spontaneously to the licensed manufacturer.
(f) Reporting forms. (1) Except as provided in paragraph (f)(3) of
this section, the licensed manufacturer shall complete the reporting
form designated by FDA for each report of an adverse experience (FDA
Form 3500A, or, for vaccines, a VAERS form; foreign events including
those associated with the use of vaccines, may be submitted either on an
FDA Form 3500A or, if preferred, on a CIOMS I form).
(2) Each completed form should refer only to an individual patient
or single attached publication.
(3) Instead of using a designated reporting form, a licensed
manufacturer may use a computer-generated form or other alternative
format (e.g., a computer-generated tape or tabular listing) provided
that:
(i) The content of the alternative format is equivalent in all
elements of information to those specified in the form designated by
FDA; and
(ii) the format is approved in advance by MEDWATCH: The FDA Medical
Products Reporting Program; or, for alternatives to the VAERS Form, by
the Division of Biostatistics and Epidemiology.
(4) Copies of the reporting form designated by FDA (FDA-3500A) for
nonvaccine biological products may be obtained from http://www.fda.gov/
medwatch/getforms.htm. Additional supplies of the form may be obtained
from the Consolidated Forms and Publications Distribution Center, 3222
Hubbard Rd., Landover, MD 20785. Supplies of the VAERS form may be
obtained from VAERS by calling 1-800-822-7967.
(g) Multiple reports. A licensed manufacturer should not include in
reports under this section any adverse experience that occurred in
clinical trials if they were previously submitted as part of the
biologics license application. If a report refers to more than one
biological product marketed by a licensed manufacturer, the licensed
manufacturer should submit the report to the biologics license
application for the product listed first in the report.
(h) Patient privacy. For nonvaccine biological products, a licensed
manufacturer should not include in reports under this section the names
and addresses of individual patients; instead,
[[Page 20]]
the licensed manufacturer should assign a unique code number to each
report, preferably not more than eight characters in length. The
licensed manufacturer should include the name of the reporter from whom
the information was received. The names of patients, health care
professionals, hospitals, and geographical identifiers in adverse
experience reports are not releasable to the public under FDA's public
information regulations in part 20 this of chapter. For vaccine adverse
experience reports, these data will become part of the CDC Privacy Act
System 09-20-0136, ``Epidemiologic Studies and Surveillance of Disease
Problems.'' Information identifying the person who received the vaccine
or that person's legal representative will not be made available to the
public, but may be available to the vaccinee or legal representative.
(i) Recordkeeping. The licensed manufacturer shall maintain for a
period of 10 years records of all adverse experiences known to the
licensed manufacturer, including raw data and any correspondence
relating to the adverse experiences.
(j) Revocation of biologics license. If a licensed manufacturer
fails to establish and maintain records and make reports required under
this section with respect to a licensed biological product, FDA may
revoke the biologics license for such a product in accordance with the
procedures of Sec. 601.5 of this chapter.
(k) Exemptions. Manufacturers of the following listed products are
not required to submit adverse experience reports under this section:
(1) Whole blood or components of whole blood.
(2) In vitro diagnostic products, including assay systems for the
detection of antibodies or antigens to retroviruses. These products are
subject to the reporting requirements for devices.
(l) Disclaimer. A report or information submitted by a licensed
manufacturer under this section (and any release by FDA of that report
or information) does not necessarily reflect a conclusion by the
licensed manufacturer or FDA that the report or information constitutes
an admission that the biological product caused or contributed to an
adverse effect. A licensed manufacturer need not admit, and may deny,
that the report or information submitted under this section constitutes
an admission that the biological product caused or contributed to an
adverse effect. For purposes of this provision, this paragraph also
includes any person reporting under paragraph (c)(1)(iii) of this
section.
[59 FR 54042, Oct. 27, 1994, as amended at 62 FR 34168, June 25, 1997;
62 FR 52252, Oct. 7, 1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449, Oct.
20, 1999; 70 FR 14982, Mar. 24, 2005]
Sec. 600.81 Distribution reports.
The licensed manufacturer shall submit to the Center for Biologics
Evaluation and Research or the Center for Drug Evaluation and Research
(see mailing addresses in Sec. 600.2), information about the quantity
of the product distributed under the biologics license, including the
quantity distributed to distributors. The interval between distribution
reports shall be 6 months. Upon written notice, FDA may require that the
licensed manufacturer submit distribution reports under this section at
times other than every 6 months. The distribution report shall consist
of the bulk lot number (from which the final container was filled), the
fill lot numbers for the total number of dosage units of each strength
or potency distributed (e.g., fifty thousand per 10-milliliter vials),
the label lot number (if different from fill lot number), labeled date
of expiration, number of doses in fill lot/label lot, date of release of
fill lot/label lot for distribution at that time. If any significant
amount of a fill lot/label lot is returned, include this information.
Disclosure of financial or pricing data is not required. As needed, FDA
may require submission of more detailed product distribution
information. Upon written notice, FDA may require that the licensed
manufacturer submit reports under this section at times other than those
stated. Requests by a licensed manufacturer to submit reports at times
other than those stated should be made as a request for a waiver under
Sec. 600.90.
[59 FR 54042, Oct. 27, 1994, as amended at 64 FR 56449, Oct. 20, 1999;
70 FR 14983, Mar. 24, 2005]
[[Page 21]]
Sec. 600.90 Waivers.
(a) A licensed manufacturer may ask the Food and Drug Administration
to waive under this section any requirement that applies to the licensed
manufacturer under Sec. Sec. 600.80 and 600.81. A waiver request under
this section is required to be submitted with supporting documentation.
The waiver request is required to contain one of the following:
(1) An explanation why the licensed manufacturer's compliance with
the requirement is unnecessary or cannot be achieved,
(2) A description of an alternative submission that satisfies the
purpose of the requirement, or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds one of the following:
(1) The licensed manufacturer's compliance with the requirement is
unnecessary or cannot be achieved,
(2) The licensed manufacturer's alternative submission satisfies the
requirement, or
(3) The licensed manufacturer's submission otherwise justifies a
waiver.
PART 601_LICENSING--Table of Contents
Subpart A_General Provisions
Sec.
601.2 Applications for biologics licenses; procedures for filing.
601.3 Complete response letter to the applicant.
601.4 Issuance and denial of license.
601.5 Revocation of license.
601.6 Suspension of license.
601.7 Procedure for hearings.
601.8 Publication of revocation.
601.9 Licenses; reissuance.
Subpart B [Reserved]
Subpart C_Biologics Licensing
601.12 Changes to an approved application.
601.14 Regulatory submissions in electronic format.
601.15 Foreign establishments and products: Samples for each
importation.
601.20 Biologics licenses; issuance and conditions.
601.21 Products under development.
601.22 Products in short supply; initial manufacturing at other than
licensed location.
601.25 Review procedures to determine that licensed biological products
are safe, effective, and not misbranded under prescribed,
recommended, or suggested conditions of use.
601.26 Reclassification procedures to determine that licensed biological
products are safe, effective, and not misbranded under
prescribed, recommended, or suggested conditions of use.
601.27 Pediatric studies.
601.28 Annual reports of postmarketing pediatric studies.
601.29 Guidance documents.
Subpart D_Diagnostic Radiopharmaceuticals
601.30 Scope.
601.31 Definition.
601.32 General factors relevant to safety and effectiveness.
601.33 Indications.
601.34 Evaluation of effectiveness.
601.35 Evaluation of safety.
Subpart E_Accelerated Approval of Biological Products for Serious or
Life-Threatening Illnesses
601.40 Scope.
601.41 Approval based on a surrogate endpoint or on an effect on a
clinical endpoint other than survival or irreversible
morbidity.
601.42 Approval with restrictions to assure safe use.
601.43 Withdrawal procedures.
601.44 Postmarketing safety reporting.
601.45 Promotional materials.
601.46 Termination of requirements.
Subpart F_Confidentiality of Information
601.50 Confidentiality of data and information in an investigational new
drug notice for a biological product.
601.51 Confidentiality of data and information in applications for
biologics licenses.
Subpart G_Postmarketing Studies
601.70 Annual progress reports of postmarketing studies.
Subpart H_Approval of Biological Products When Human Efficacy Studies
Are Not Ethical or Feasible
601.90 Scope.
601.91 Approval based on evidence of effectiveness from studies in
animals.
601.92 Withdrawal procedures.
601.93 Postmarketing safety reporting.
601.94 Promotional materials.
601.95 Termination of requirements.
[[Page 22]]
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 355,
356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216,
241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C.
355 note).
Source: 38 FR 32052, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A_General Provisions
Sec. 601.2 Applications for biologics licenses; procedures for filing.
(a) General. To obtain a biologics license under section 351 of the
Public Health Service Act for any biological product, the manufacturer
shall submit an application to the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research (see mailing addresses in Sec. 600.2 of this chapter), on
forms prescribed for such purposes, and shall submit data derived from
nonclinical laboratory and clinical studies which demonstrate that the
manufactured product meets prescribed requirements of safety, purity,
and potency; with respect to each nonclinical laboratory study, either a
statement that the study was conducted in compliance with the
requirements set forth in part 58 of this chapter, or, if the study was
not conducted in compliance with such regulations, a brief statement of
the reason for the noncompliance; statements regarding each clinical
investigation involving human subjects contained in the application,
that it either was conducted in compliance with the requirements for
institutional review set forth in part 56 of this chapter; or was not
subject to such requirements in accordance with Sec. 56.104 or Sec.
56.105, and was conducted in compliance with requirements for informed
consent set forth in part 50 of this chapter. A full description of
manufacturing methods; data establishing stability of the product
through the dating period; sample(s) representative of the product for
introduction or delivery for introduction into interstate commerce;
summaries of results of tests performed on the lot(s) represented by the
submitted sample(s); specimens of the labels, enclosures, and
containers, and if applicable, any Medication Guide required under part
208 of this chapter proposed to be used for the product; and the address
of each location involved in the manufacture of the biological product
shall be listed in the biologics license application. The applicant
shall also include a financial certification or disclosure statement(s)
or both for clinical investigators as required by part 54 of this
chapter. An application for a biologics license shall not be considered
as filed until all pertinent information and data have been received by
the Food and Drug Administration. The applicant shall also include
either a claim for categorical exclusion under Sec. 25.30 or Sec.
25.31 of this chapter or an environmental assessment under Sec. 25.40
of this chapter. The applicant, or the applicant's attorney, agent, or
other authorized official shall sign the application. An application for
any of the following specified categories of biological products subject
to licensure shall be handled as set forth in paragraph (c) of this
section:
(1) Therapeutic DNA plasmid products;
(2) Therapeutic synthetic peptide products of 40 or fewer amino
acids;
(3) Monoclonal antibody products for in vivo use; and
(4) Therapeutic recombinant DNA-derived products.
(b) [Reserved]
(c)(1) To obtain marketing approval for a biological product subject
to licensure which is a therapeutic DNA plasmid product, therapeutic
synthetic peptide product of 40 or fewer amino acids, monoclonal
antibody product for in vivo use, or therapeutic recombinant DNA-derived
product, an applicant shall submit a biologics license application in
accordance with paragraph (a) of this section except that the following
sections in parts 600 through 680 of this chapter shall not be
applicable to such products: Sec. Sec. 600.10(b) and (c), 600.11,
600.12, 600.13, 610.11, 610.53, and 610.62 of this chapter.
(2) To the extent that the requirements in this paragraph (c)
conflict
[[Page 23]]
with other requirements in this subchapter, this paragraph (c) shall
supersede other requirements.
(d) Approval of a biologics license application or issuance of a
biologics license shall constitute a determination that the
establishment(s) and the product meet applicable requirements to ensure
the continued safety, purity, and potency of such products. Applicable
requirements for the maintenance of establishments for the manufacture
of a product subject to this section shall include but not be limited to
the good manufacturing practice requirements set forth in parts 210,
211, 600, 606, and 820 of this chapter.
(e) Any establishment and product license for a biological product
issued under section 351 of the Public Health Service Act (42 U.S.C. 201
et seq.) that has not been revoked or suspended as of December 20, 1999,
shall constitute an approved biologics license application in effect
under the same terms and conditions set forth in such product license
and such portions of the establishment license relating to such product.
[64 FR 56450, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]
Sec. 601.3 Complete response letter to the applicant.
(a) Complete response letter. The Food and Drug Administration will
send the biologics license applicant or supplement applicant a complete
response letter if the agency determines that it will not approve the
biologics license application or supplement in its present form.
(1) Description of specific deficiencies. A complete response letter
will describe all of the deficiencies that the agency has identified in
a biologics license application or supplement, except as stated in
paragraph (a)(2) of this section.
(2) Inadequate data. If FDA determines, after a biologics license
application or supplement is filed, that the data submitted are
inadequate to support approval, the agency might issue a complete
response letter without first conducting required inspections, testing
submitted product lots, and/or reviewing proposed product labeling.
(3) Recommendation of actions for approval. When possible, a
complete response letter will recommend actions that the applicant might
take to place its biologics license application or supplement in
condition for approval.
(b) Applicant actions. After receiving a complete response letter,
the biologics license applicant or supplement applicant must take either
of the following actions:
(1) Resubmission. Resubmit the application or supplement, addressing
all deficiencies identified in the complete response letter.
(2) Withdrawal. Withdraw the application or supplement. A decision
to withdraw the application or supplement is without prejudice to a
subsequent submission.
(c) Failure to take action. (1) FDA may consider a biologics license
applicant or supplement applicant's failure to either resubmit or
withdraw the application or supplement within 1 year after issuance of a
complete response letter to be a request by the applicant to withdraw
the application or supplement, unless the applicant has requested an
extension of time in which to resubmit the application or supplement.
FDA will grant any reasonable request for such an extension. FDA may
consider an applicant's failure to resubmit the application or
supplement within the extended time period or request an additional
extension to be a request by the applicant to withdraw the application.
(2) If FDA considers an applicant's failure to take action in
accordance with paragraph (c)(1) of this section to be a request to
withdraw the application, the agency will notify the applicant in
writing. The applicant will have 30 days from the date of the
notification to explain why the application or supplement should not be
withdrawn and to request an extension of time in which to resubmit the
application or supplement. FDA will grant any reasonable request for an
extension. If the applicant does not respond to the notification within
30 days, the application or supplement will be deemed to be withdrawn.
[73 FR 39611, July 10, 2008]
Sec. 601.4 Issuance and denial of license.
(a) A biologics license shall be issued upon a determination by the
Director,
[[Page 24]]
Center for Biologics Evaluation and Research or the Director, Center for
Drug Evaluation and Research that the establishment(s) and the product
meet the applicable requirements established in this chapter. A
biologics license shall be valid until suspended or revoked.
(b) If the Commissioner determines that the establishment or product
does not meet the requirements established in this chapter, the
biologics license application shall be denied and the applicant shall be
informed of the grounds for, and of an opportunity for a hearing on, the
decision. If the applicant so requests, the Commissioner shall issue a
notice of opportunity for hearing on the matter pursuant to Sec.
12.21(b) of this chapter.
[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42
FR 19142, Apr. 12, 1977; 64 FR 56450, Oct. 20, 1999; 70 FR 14983, Mar.
24, 2005]
Sec. 601.5 Revocation of license.
(a) A biologics license shall be revoked upon application of the
manufacturer giving notice of intention to discontinue the manufacture
of all products manufactured under such license or to discontinue the
manufacture of a particular product for which a license is held and
waiving an opportunity for a hearing on the matter.
(b)(1) The Commissioner shall notify the licensed manufacturer of
the intention to revoke the biologics license, setting forth the grounds
for, and offering an opportunity for a hearing on the proposed
revocation if the Commissioner finds any of the following:
(i) Authorized Food and Drug Administration employees after
reasonable efforts have been unable to gain access to an establishment
or a location for the purpose of carrying out the inspection required
under Sec. 600.21 of this chapter,
(ii) Manufacturing of products or of a product has been discontinued
to an extent that a meaningful inspection or evaluation cannot be made,
(iii) The manufacturer has failed to report a change as required by
Sec. 601.12 of this chapter,
(iv) The establishment or any location thereof, or the product for
which the license has been issued, fails to conform to the applicable
standards established in the license and in this chapter designed to
ensure the continued safety, purity, and potency of the manufactured
product,
(v) The establishment or the manufacturing methods have been so
changed as to require a new showing that the establishment or product
meets the requirements established in this chapter in order to protect
the public health, or
(vi) The licensed product is not safe and effective for all of its
intended uses or is misbranded with respect to any such use.
(2) Except as provided in Sec. 601.6 of this chapter, or in cases
involving willfulness, the notification required in this paragraph shall
provide a reasonable period for the licensed manufacturer to demonstrate
or achieve compliance with the requirements of this chapter, before
proceedings will be instituted for the revocation of the license. If
compliance is not demonstrated or achieved and the licensed manufacturer
does not waive the opportunity for a hearing, the Commissioner shall
issue a notice of opportunity for hearing on the matter under Sec.
12.21(b) of this chapter.
[64 FR 56451, Oct. 20, 1999]
Sec. 601.6 Suspension of license.
(a) Whenever the Commissioner has reasonable grounds to believe that
any of the grounds for revocation of a license exist and that by reason
thereof there is a danger to health, the Commissioner may notify the
licensed manufacturer that the biologics license is suspended and
require that the licensed manufacturer do the following:
(1) Notify the selling agents and distributors to whom such product
or products have been delivered of such suspension, and
(2) Furnish to the Center for Biologics Evaluation and Research or
the Center for Drug Evaluation and Research, complete records of such
deliveries and notice of suspension.
(b) Upon suspension of a license, the Commissioner shall either:
(1) Proceed under the provisions of Sec. 601.5(b) of this chapter
to revoke the license, or
[[Page 25]]
(2) If the licensed manufacturer agrees, hold revocation in abeyance
pending resolution of the matters involved.
[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]
Sec. 601.7 Procedure for hearings.
(a) A notice of opportunity for hearing, notice of appearance and
request for hearing, and grant or denial of hearing for a biological
drug pursuant to this part, for which the exemption from the Federal
Food, Drug, and Cosmetic Act in Sec. 310.4 of this chapter has been
revoked, shall be subject to the provisions of Sec. 314.200 of this
chapter except to the extent that the notice of opportunity for hearing
on the matter issued pursuant to Sec. 12.21(b) of this chapter
specifically provides otherwise.
(b) Hearings pursuant to Sec. Sec. 601.4 through 601.6 shall be
governed by part 12 of this chapter.
(c) When a license has been suspended pursuant to Sec. 601.6 and a
hearing request has been granted, the hearing shall proceed on an
expedited basis.
[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42
FR 19143, Apr. 12, 1977]
Sec. 601.8 Publication of revocation.
The Commissioner, following revocation of a biologics license under
21 CFR 601.5(b), will publish a notice in the Federal Register with a
statement of the specific grounds for the revocation.
[74 FR 20585, May 5, 2009]
Sec. 601.9 Licenses; reissuance.
(a) Compliance with requirements. A biologics license, previously
suspended or revoked, may be reissued or reinstated upon a showing of
compliance with requirements and upon such inspection and examination as
may be considered necessary by the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research.
(b) Exclusion of noncomplying location. A biologics license,
excluding a location or locations that fail to comply with the
requirements in this chapter, may be issued without further application
and concurrently with the suspension or revocation of the license for
noncompliance at the excluded location or locations.
(c) Exclusion of noncomplying product(s). In the case of multiple
products included under a single biologics license application, a
biologics license may be issued, excluding the noncompliant product(s),
without further application and concurrently with the suspension or
revocation of the biologics license for a noncompliant product(s).
[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]
Subpart B [Reserved]
Subpart C_Biologics Licensing
Sec. 601.12 Changes to an approved application.
(a) General. (1) As provided by this section, an applicant must
inform the Food and Drug Administration (FDA) (see mailing addresses in
Sec. 600.2 of this chapter) about each change in the product,
production process, quality controls, equipment, facilities, responsible
personnel, or labeling established in the approved license
application(s).
(2) Before distributing a product made using a change, an applicant
must assess the effects of the change and demonstrate through
appropriate validation and/or other clinical and/or nonclinical
laboratory studies the lack of adverse effect of the change on the
identity, strength, quality, purity, or potency of the product as they
may relate to the safety or effectiveness of the product.
(3) Notwithstanding the requirements of paragraphs (b), (c), and (f)
of this section, an applicant must make a change provided for in those
paragraphs in accordance with a regulation or guidance that provides for
a less burdensome notification of the change (for example, by submission
of a supplement that does not require approval prior to distribution of
the product or in an annual report).
(4) The applicant must promptly revise all promotional labeling and
advertising to make it consistent with any labeling change implemented
in accordance with paragraphs (f)(1) and (f)(2) of this section.
[[Page 26]]
(5) A supplement or annual report must include a list of all changes
contained in the supplement or annual report. For supplements, this list
must be provided in the cover letter.
(b) Changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes). (1) A
supplement shall be submitted for any change in the product, production
process, quality controls, equipment, facilities, or responsible
personnel that has a substantial potential to have an adverse effect on
the identity, strength, quality, purity, or potency of the product as
they may relate to the safety or effectiveness of the product.
(2) These changes include, but are not limited to:
(i) Except as provided in paragraphs (c) and (d) of this section,
changes in the qualitative or quantitative formulation, including
inactive ingredients, or in the specifications provided in the approved
application;
(ii) Changes requiring completion of an appropriate human study to
demonstrate the equivalence of the identity, strength, quality, purity,
or potency of the product as they may relate to the safety or
effectiveness of the product;
(iii) Changes in the virus or adventitious agent removal or
inactivation method(s);
(iv) Changes in the source material or cell line;
(v) Establishment of a new master cell bank or seed; and
(vi) Changes which may affect product sterility assurance, such as
changes in product or component sterilization method(s), or an addition,
deletion, or substitution of steps in an aseptic processing operation.
(3) The applicant must obtain approval of the supplement from FDA
prior to distribution of the product made using the change. Except for
submissions under paragraph (e) of this section, the following shall be
contained in the supplement:
(i) A detailed description of the proposed change;
(ii) The product(s) involved;
(iii) The manufacturing site(s) or area(s) affected;
(iv) A description of the methods used and studies performed to
evaluate the effect of the change on the identity, strength, quality,
purity, or potency of the product as they may relate to the safety or
effectiveness of the product;
(v) The data derived from such studies;
(vi) Relevant validation protocols and data; and
(vii) A reference list of relevant standard operating procedures
(SOP's).
(4) An applicant may ask FDA to expedite its review of a supplement
for public health reasons or if a delay in making the change described
in it would impose an extraordinary hardship on the applicant. Such a
supplement and its mailing cover should be plainly marked: ``Prior
Approval Supplement-Expedited Review Requested.
(c) Changes requiring supplement submission at least 30 days prior
to distribution of the product made using the change. (1) A supplement
shall be submitted for any change in the product, production process,
quality controls, equipment, facilities, or responsible personnel that
has a moderate potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as they may relate
to the safety or effectiveness of the product. The supplement shall be
labeled ``Supplement--Changes Being Effected in 30 Days'' or, if
applicable under paragraph (c)(5) of this section, ``Supplement--Changes
Being Effected.''
(2) These changes include, but are not limited to:
(i) [Reserved]
(ii) An increase or decrease in production scale during finishing
steps that involves different equipment; and
(iii) Replacement of equipment with that of similar, but not
identical, design and operating principle that does not affect the
process methodology or process operating parameters.
(iv) Relaxation of an acceptance criterion or deletion of a test to
comply with an official compendium that is consistent with FDA statutory
and regulatory requirements.
(3) Pending approval of the supplement by FDA, and except as
provided
[[Page 27]]
in paragraph (c)(5) of this section, distribution of the product made
using the change may begin not less than 30 days after receipt of the
supplement by FDA. The information listed in paragraph (b)(3)(i) through
(b)(3)(vii) of this section shall be contained in the supplement.
(4) If within 30 days following FDA's receipt of the supplement, FDA
informs the applicant that either:
(i) The change requires approval prior to distribution of the
product in accordance with paragraph (b) of this section; or
(ii) Any of the information required under paragraph (c)(3) of this
section is missing; the applicant shall not distribute the product made
using the change until FDA determines that compliance with this section
is achieved.
(5) In certain circumstances, FDA may determine that, based on
experience with a particular type of change, the supplement for such
change is usually complete and provides the proper information, and on
particular assurances that the proposed change has been appropriately
submitted, the product made using the change may be distributed
immediately upon receipt of the supplement by FDA. These circumstances
may include substantial similarity with a type of change regularly
involving a ``Supplement--Changes Being Effected'' supplement or a
situation in which the applicant presents evidence that the proposed
change has been validated in accordance with an approved protocol for
such change under paragraph (e) of this section.
(6) If the agency disapproves the supplemental application, it may
order the manufacturer to cease distribution of the products made with
the manufacturing change.
(d) Changes to be described in an annual report (minor changes). (1)
Changes in the product, production process, quality controls, equipment,
facilities, or responsible personnel that have a minimal potential to
have an adverse effect on the identity, strength, quality, purity, or
potency of the product as they may relate to the safety or effectiveness
of the product shall be documented by the applicant in an annual report
submitted each year within 60 days of the anniversary date of approval
of the application. The Director, Center for Biologics Evaluation and
Research or the Director, Center for Drug Evaluation and Research, may
approve a written request for an alternative date to combine annual
reports for multiple approved applications into a single annual report
submission.
(2) These changes include, but are not limited to:
(i) Any change made to comply with a change to an official
compendium, except a change described in paragraph (c)(2)(iv) of this
section, that is consistent with FDA statutory and regulatory
requirements.
(ii) The deletion or reduction of an ingredient intended only to
affect the color of the product, except that a change intended only to
affect Blood Grouping Reagents requires supplement submission and
approval prior to distribution of the product made using the change in
accordance with the requirements set forth in paragraph (b) of this
section;
(iii) An extension of an expiration dating period based upon full
shelf life data on production batches obtained from a protocol approved
in the application;
(iv) A change within the container closure system for a nonsterile
product, based upon a showing of equivalency to the approved system
under a protocol approved in the application or published in an official
compendium;
(v) A change in the size and/or shape of a container containing the
same number of dosage units for a nonsterile solid dosage form product,
without a change from one container closure system to another;
(vi) The addition by embossing, debossing, or engraving of a code
imprint to a solid dosage form biological product other than a modified
release dosage form, or a minor change in an existing code imprint; and
(vii) The addition or revision of an alternative analytical
procedure that provides the same or increased assurance of the identity,
strength, quality, purity, or potency of the material
[[Page 28]]
being tested as the analytical procedure described in the approved
application, or deletion of an alternative analytical procedure.
(3) The following information for each change shall be contained in
the annual report:
(i) A list of all products involved; and
(ii) A full description of the manufacturing and controls changes
including: the manufacturing site(s) or area(s) involved; the date the
change was made; a cross-reference to relevant validation protocols and/
or SOP's; and relevant data from studies and tests performed to evaluate
the effect of the change on the identity, strength, quality, purity, or
potency of the product as they may relate to the safety or effectiveness
of the product.
(iii) A statement by the holder of the approved application or
license that the effects of the change have been assessed.
(4) The applicant shall submit the report to the FDA office
responsible for reviewing the application. The report shall include all
the information required under this paragraph for each change made
during the annual reporting interval which ends on the anniversary date
in the order in which they were implemented.
(e) An applicant may submit one or more protocols describing the
specific tests and validation studies and acceptable limits to be
achieved to demonstrate the lack of adverse effect for specified types
of manufacturing changes on the identity, strength, quality, purity, or
potency of the product as they may relate to the safety or effectiveness
of the product. Any such protocols, or change to a protocol, shall be
submitted as a supplement requiring approval from FDA prior to
distribution of the product which, if approved, may justify a reduced
reporting category for the particular change because the use of the
protocol for that type of change reduces the potential risk of an
adverse effect.
(f) Labeling changes. (1) Labeling changes requiring supplement
submission--FDA approval must be obtained before distribution of the
product with the labeling change. Except as described in paragraphs
(f)(2) and (f)(3) of this section, an applicant shall submit a
supplement describing a proposed change in the package insert, package
label, container label, or, if applicable, a Medication Guide required
under part 208 of this chapter, and include the information necessary to
support the proposed change. An applicant cannot use paragraph (f)(2) of
this section to make any change to the information required in Sec.
201.57(a) of this chapter. An applicant may report the minor changes to
the information specified in paragraph (f)(3)(i)(D) of this section in
an annual report. The supplement shall clearly highlight the proposed
change in the labeling. The applicant shall obtain approval from FDA
prior to distribution of the product with the labeling change.
(2) Labeling changes requiring supplement submission--product with a
labeling change that may be distributed before FDA approval. (i) An
applicant shall submit, at the time such change is made, a supplement
for any change in the package insert, package label, or container label
to reflect newly acquired information, except for changes to the package
insert required in Sec. 201.57(a) of this chapter (which must be made
under paragraph (f)(1) of this section), to accomplish any of the
following:
(A) To add or strengthen a contraindication, warning, precaution, or
adverse reaction for which the evidence of a causal association
satisfies the standard for inclusion in the labeling under Sec.
201.57(c) of this chapter;
(B) To add or strengthen a statement about abuse, dependence,
psychological effect, or overdosage;
(C) To add or strengthen an instruction about dosage and
administration that is intended to increase the safety of the use of the
product; and
(D) To delete false, misleading, or unsupported indications for use
or claims for effectiveness.
(E) Any labeling change normally requiring a supplement submission
and approval prior to distribution of the product that FDA specifically
requests be submitted under this provision.
(ii) Pending approval of the supplement by FDA, the applicant may
distribute a product with a package insert, package label, or container
label bearing such change at the time the
[[Page 29]]
supplement is submitted. The supplement shall clearly identify the
change being made and include necessary supporting data. The supplement
and its mailing cover shall be plainly marked: ``Special Labeling
Supplement--Changes Being Effected.''
(3) Labeling changes requiring submission in an annual report. (i)
An applicant shall submit any final printed package insert, package
label, container label, or Medication Guide required under part 208 of
this chapter incorporating the following changes in an annual report
submitted to FDA each year as provided in paragraph (d)(1) of this
section:
(A) Editorial or similar minor changes;
(B) A change in the information on how the product is supplied that
does not involve a change in the dosage strength or dosage form;
(C) A change in the information specified in Sec. 208.20(b)(8)(iii)
and (b)(8)(iv) of this chapter for a Medication Guide; and
(D) A change to the information required in Sec. 201.57(a) of this
chapter as follows:
(1) Removal of a listed section(s) specified in Sec. 201.57(a)(5)
of this chapter; and
(2) Changes to the most recent revision date of the labeling as
specified in Sec. 201.57(a)(15) of this chapter.
(E) A change made pursuant to an exception or alternative granted
under Sec. 201.26 or Sec. 610.68 of this chapter.
(ii) The applicant may distribute a product with a package insert,
package label, or container label bearing such change at the time the
change is made.
(4) Advertisements and promotional labeling. Advertisements and
promotional labeling shall be submitted to the Center for Biologics
Evaluation and Research or Center for Drug Evaluation and Research in
accordance with the requirements set forth in Sec. 314.81(b)(3)(i) of
this chapter, except that Form FDA-2567 (Transmittal of Labels and
Circulars) or an equivalent form shall be used.
(5) The submission and grant of a written request for an exception
or alternative under Sec. 201.26 or Sec. 610.68 of this chapter
satisfies the requirements in paragraphs (f)(1) through (f)(2) of this
section.
(6) For purposes of paragraph (f)(2) of this section, information
will be considered newly acquired if it consists of data, analyses, or
other information not previously submitted to the agency, which may
include (but are not limited to) data derived from new clinical studies,
reports of adverse events, or new analyses of previously submitted data
(e.g., meta-analyses) if the studies, events or analyses reveal risks of
a different type or greater severity or frequency than previously
included in submissions to FDA.
(g) Failure to comply. In addition to other remedies available in
law and regulations, in the event of repeated failure of the applicant
to comply with this section, FDA may require that the applicant submit a
supplement for any proposed change and obtain approval of the supplement
by FDA prior to distribution of the product made using the change.
(h) Administrative review. Under Sec. 10.75 of this chapter, an
applicant may request internal FDA review of FDA employee decisions
under this section.
[62 FR 39901, July 24, 1997, as amended at 63 FR 66399, Dec. 1, 1998.
Redesignated at 65 FR 59718, Oct. 6, 2000, and amended at 69 FR 18766,
Apr. 8, 2004; 70 FR 14983, Mar. 24, 2005; 71 FR 3997, Jan. 24, 2006; 72
FR 73600, Dec. 28, 2007; 73 FR 49609, Aug. 22, 2008; 73 FR 68333, Nov.
18, 2008]
Sec. 601.14 Regulatory submissions in electronic format.
(a) General. Electronic format submissions must be in a form that
FDA can process, review, and archive. FDA will periodically issue
guidance on how to provide the electronic submission (e.g., method of
transmission, media, file formats, preparation and organization of
files.)
(b) Labeling. The content of labeling required under Sec.
201.100(d)(3) of this chapter (commonly referred to as the package
insert or professional labeling), including all text, tables, and
figures, must be submitted to the agency in electronic format as
described in paragraph (a) of this section. This requirement is in
addition to the provisions of Sec. Sec. 601.2(a) and 601.12(f) that
require applicants to submit specimens
[[Page 30]]
of the labels, enclosures, and containers, or to submit other final
printed labeling. Submissions under this paragraph must be made in
accordance with part 11 of this chapter except for the requirements of
Sec. 11.10(a), (c) through (h), and (k), and the corresponding
requirements of Sec. 11.30.
[68 FR 69020, Dec. 11, 2003]
Sec. 601.15 Foreign establishments and products: samples for each
importation.
Random samples of each importation, obtained by the District
Director of Customs and forwarded to the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research (see mailing addresses in Sec. 600.2 of this chapter) must be
at least two final containers of each lot of product. A copy of the
associated documents which describe and identify the shipment must
accompany the shipment for forwarding with the samples to the Director,
Center for Biologics Evaluation and Research or the Director, Center for
Drug Evaluation and Research (see mailing addresses in Sec. 600.2). For
shipments of 20 or less final containers, samples need not be forwarded,
provided a copy of an official release from the Center for Biologics
Evaluation and Research or Center for Drug Evaluation and Research
accompanies each shipment.
[70 FR 14983, Mar. 24, 2005]
Sec. 601.20 Biologics licenses; issuance and conditions.
(a) Examination--compliance with requirements. A biologics license
application shall be approved only upon examination of the product and
upon a determination that the product complies with the standards
established in the biologics license application and the requirements
prescribed in the regulations in this chapter including but not limited
to the good manufacturing practice requirements set forth in parts 210,
211, 600, 606, and 820 of this chapter.
(b) Availability of product. No biologics license shall be issued
unless:
(1) The product intended for introduction into interstate commerce
is available for examination, and
(2) Such product is available for inspection during all phases of
manufacture.
(c) Manufacturing process--impairment of assurances. No product
shall be licensed if any part of the process of or relating to the
manufacture of such product, in the judgment of the Director, Center for
Biologics Evaluation and Research or the Director, Center for Drug
Evaluation and Research, would impair the assurances of continued
safety, purity, and potency as provided by the regulations contained in
this chapter.
(d) Inspection--compliance with requirements. A biologics license
shall be issued or a biologics license application approved only after
inspection of the establishment(s) listed in the biologics license
application and upon a determination that the establishment(s) complies
with the standards established in the biologics license application and
the requirements prescribed in applicable regulations.
(e) One biologics license to cover all locations. One biologics
license shall be issued to cover all locations meeting the establishment
standards identified in the approved biologics license application and
each location shall be subject to inspection by FDA officials.
[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]
Sec. 601.21 Products under development.
A biological product undergoing development, but not yet ready for a
biologics license, may be shipped or otherwise delivered from one State
or possession into another State or possession provided such shipment or
delivery is not for introduction or delivery for introduction into
interstate commerce, except as provided in sections 505(i) and 520(g) of
the Federal Food, Drug, and Cosmetic Act, as amended, and the
regulations thereunder (21 CFR parts 312 and 812).
[64 FR 56451, Oct. 20, 1999]
[[Page 31]]
Sec. 601.22 Products in short supply; initial manufacturing at other than
licensed location.
A biologics license issued to a manufacturer and covering all
locations of manufacture shall authorize persons other than such
manufacturer to conduct at places other than such locations the initial,
and partial manufacturing of a product for shipment solely to such
manufacturer only to the extent that the names of such persons and
places are registered with the Commissioner of Food and Drugs and it is
found upon application of such manufacturer, that the product is in
short supply due either to the peculiar growth requirements of the
organism involved or to the scarcity of the animal required for
manufacturing purposes, and such manufacturer has established with
respect to such persons and places such procedures, inspections, tests
or other arrangements as will ensure full compliance with the applicable
regulations of this subchapter related to continued safety, purity, and
potency. Such persons and places shall be subject to all regulations of
this subchapter except Sec. Sec. 601.2 to 601.6, 601.9, 601.10, 601.20,
601.21 to 601.33, and 610.60 to 610.65 of this chapter. For persons and
places authorized under this section to conduct the initial and partial
manufacturing of a product for shipment solely to a manufacturer of a
product subject to licensure under Sec. 601.2(c), the following
additional regulations shall not be applicable: Sec. Sec. 600.10(b) and
(c), 600.11, 600.12, 600.13, 610.11, and 610.53 of this chapter. Failure
of such manufacturer to maintain such procedures, inspections, tests, or
other arrangements, or failure of any person conducting such partial
manufacturing to comply with applicable regulations shall constitute a
ground for suspension or revocation of the authority conferred pursuant
to this section on the same basis as provided in Sec. Sec. 601.6 to
601.8 with respect to the suspension and the revocation of licenses.
[42 FR 4718, Jan. 25, 1977, as amended at 61 FR 24233, May 14, 1996; 64
FR 56452, Oct. 20, 1999]
Sec. 601.25 Review procedures to determine that licensed biological products
are safe, effective, and not misbranded under prescribed, recommended, or
suggested conditions of use.
For purposes of reviewing biological products that have been
licensed prior to July 1, 1972, to determine that they are safe and
effective and not misbranded, the following regulations shall apply.
Prior administrative action exempting biological products from the
provisions of the Federal Food, Drug, and Cosmetic Act is superseded to
the extent that these regulations result in imposing requirements
pursuant to provisions therein for a designated biological product or
category of products.
(a) Advisory review panels. The Commissioner of Food and Drugs shall
appoint advisory review panels (1) to evaluate the safety and
effectiveness of biological products for which a license has been issued
pursuant to section 351 of the Public Health Service Act, (2) to review
the labeling of such biological products, and (3) to advise him on which
of the biological products under review are safe, effective, and not
misbranded. An advisory review panel shall be established for each
designated category of biological product. The members of a panel shall
be qualified experts, appointed by the Commissioner, and shall include
persons from lists submitted by organizations representing professional,
consumer, and industry interests. Such persons shall represent a wide
divergence of responsible medical and scientific opinion. The
Commissioner shall designate the chairman of each panel, and summary
minutes of all meetings shall be made.
(b) Request for data and views. (1) The Commissioner of Food and
Drugs will publish a notice in the Federal Register requesting
interested persons to submit, for review and evaluation by an advisory
review panel, published and unpublished data and information pertinent
to a designated category of biological products.
(2) Data and information submitted pursuant to a published notice,
and falling within the confidentiality provisions of 18 U.S.C. 1905, 5
U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by
[[Page 32]]
the advisory review panel and the Food and Drug Administration as
confidential until publication of a proposed evaluation of the biologics
under review and the full report or reports of the panel. Thirty days
thereafter such data and information shall be made publicly available
and may be viewed at the Division of Dockets Management of the Food and
Drug Administration, except to the extent that the person submitting it
demonstrates that it still falls within the confidentiality provisions
of one or more of those statutes.
(3) To be considered, 12 copies of the submission on any marketed
biological product within the class shall be submitted, preferably
bound, indexed, and on standard sized paper, approximately 8\1/2\ x 11
inches. The time allotted for submissions will be 60 days, unless
otherwise indicated in the specific notice requesting data and views for
a particular category of biological products. When requested,
abbreviated submissions should be sent. All submissions shall be in the
following format, indicating ``none'' or ``not applicable'' where
appropriate, unless changed in the Federal Register notice:
Biological Products Review Information
I. Label or labels and all other labeling (preferably mounted.
Facsimile labeling is acceptable in lieu of actual container labeling),
including labeling for export.
II. Representative advertising used during the past 5 years.
III. The complete quantitative composition of the biological
product.
IV. Animal safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
V. Human safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the safety of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the safety of combinations of the individual active
components.
5. Pertinent medical and scientific literature.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the safety of the finished biological product.
5. Pertinent medical and scientific literature.
VI. Efficacy data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination on the efficacy of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the effectiveness of combinations of the individual
active components.
5. Pertinent medical and scientific literature.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a
determination as to the effectiveness of the finished biological
product.
5. Pertinent medical and scientific literature.
VII. A summary of the data and views setting forth the medical
rational and purpose (or lack thereof) for the biological product and
its components and the scientific basis (or lack thereof) for the
conclusion that the biological product, including its components,
[[Page 33]]
has been proven safe and effective and is properly labeled for the
intended use or uses. If there is an absence of controlled studies in
the materials submitted, an explanation as to why such studies are not
considered necessary or feasible shall be included.
VIII. If the submission is by a licensed manufacturer, a statement
signed by the authorized official of the licensed manufacturer shall be
included, stating that to the best of his or her knowledge and belief,
it includes all information, favorable and unfavorable, pertinent to an
evaluation of the safety, effectiveness, and labeling of the product,
including information derived from investigation, commercial marketing,
or published literature. If the submission is by an interested person
other than a licensed manufacturer, a statement signed by the person
responsible for such submission shall be included, stating that to the
best of his knowledge and belief, it fairly reflects a balance of all
the available information, favorable and unfavorable available to him,
pertinent to an evaluation of the safety, effectiveness, and labeling of
the product.
(c) Deliberations of an advisory review panel. An advisory review
panel will meet as often and for as long as is appropriate to review the
data submitted to it and to prepare a report containing its conclusions
and recommendations to the Commissioner of Food and Drugs with respect
to the safety, effectiveness, and labeling of the biological products in
the designated category under review.
(1) A panel may also consult any individual or group.
(2) Any interested person may request in writing an opportunity to
present oral views to the panel. Such written requests for oral
presentations should include a summarization of the data to be presented
to the panel. Such request may be granted or denied by the panel.
(3) Any interested person may present written data and views which
shall be considered by the panel. This information shall be presented to
the panel in the format set forth in paragraph (b)(3) of this section
and within the time period established for the biological product
category in the notice for review by a panel.
(d) Standards for safety, effectiveness, and labeling. The advisory
review panel, in reviewing the submitted data and preparing the panel's
conclusions and recommendations, and the Commissioner of Food and Drugs,
in reviewing and implementing the conclusions and recommendations of the
panel, shall apply the following standards to determine that a
biological product is safe and effective and not misbranded.
(1) Safety means the relative freedom from harmful effect to persons
affected, directly or indirectly, by a product when prudently
administered, taking into consideration the character of the product in
relation to the condition of the recipient at the time. Proof of safety
shall consist of adequate tests by methods reasonably applicable to show
the biological product is safe under the prescribed conditions of use,
including results of significant human experience during use.
(2) Effectiveness means a reasonable expectation that, in a
significant proportion of the target population, the pharmacological or
other effect of the biological product, when used under adequate
directions, for use and warnings against unsafe use, will serve a
clinically significant function in the diagnosis, cure, mitigation,
treatment, or prevention of disease in man. Proof of effectiveness shall
consist of controlled clinical investigations as defined in Sec.
314.126 of this chapter, unless this requirement is waived on the basis
of a showing that it is not reasonably applicable to the biological
product or essential to the validity of the investigation, and that an
alternative method of investigation is adequate to substantiate
effectiveness. Alternate methods, such as serological response
evaluation in clinical studies and appropriate animal and other
laboratory assay evaluations may be adequate to substantiate
effectiveness where a previously accepted correlation between data
generated in this way and clinical effectiveness already exists.
Investigations may be corroborated by partially controlled or
uncontrolled studies, documented clinical studies by qualified experts,
and reports of significant human experience during marketing. Isolated
case reports, random experience, and reports lacking the details which
permit scientific evaluation will not be considered.
(3) The benefit-to-risk ratio of a biological product shall be
considered in determining safety and effectiveness.
[[Page 34]]
(4) A biological product may combine two or more safe and effective
active components: (i) When each active component makes a contribution
to the claimed effect or effects; (ii) when combining of the active
ingredients does not decrease the purity, potency, safety, or
effectiveness of any of the individual active components; and (iii) if
the combination, when used under adequate directions for use and
warnings against unsafe use, provides rational concurrent preventive
therapy or treatment for a significant proportion of the target
population.
(5) Labeling shall be clear and truthful in all respects and may not
be false or misleading in any particular. It shall comply with section
351 of the Public Health Service Act and sections 502 and 503 of the
Federal Food, Drug, and Cosmetic Act, and in particular with the
applicable requirements of Sec. Sec. 610.60 through 610.65 and subpart
D of part 201 of this chapter.
(e) Advisory review panel report to the Commissioner. An advisory
review panel shall submit to the Commissioner of Food and Drugs a report
containing the panel's conclusions and recommendations with respect to
the biological products falling within the category covered by the
panel. Included within this report shall be:
(1) A statement which designates those biological products
determined by the panel to be safe and effective and not misbranded.
This statement may include any condition relating to active components,
labeling, tests required prior to release of lots, product standards, or
other conditions necessary or appropriate for their safety and
effectiveness.
(2) A statement which designates those biological products
determined by the panel to be unsafe or ineffective, or to be
misbranded. The statement shall include the panel's reasons for each
such determination.
(3) A statement which designates those biological products
determined by the panel not to fall within either paragraph (e) (1) or
(2) of this section on the basis of the panel's conclusion that the
available data are insufficient to classify such biological products,
and for which further testing is therefore required. The report shall
recommend with as must specificity as possible the type of further
testing required and the time period within which it might reasonably be
concluded. The report shall also recommend whether the product license
should or should not be revoked, thus permitting or denying continued
manufacturing and marketing of the biological product pending completion
of the testing. This recommendation will be based on an assessment of
the present evidence of the safety and effectiveness of the product and
the potential benefits and risks likely to result from the continued use
of the product for a limited period of time while the questions raised
concerning the product are being resolved by further study. \2\
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\2\ As of November 4, 1982, the provisions under paragraphs (e)(3)
and (f)(3) of this section for the interim marketing of certain
biological products pending completion of additional studies have been
superseded by the review and reclassification procedures under Sec.
601.26 of this chapter. The superseded text is included for the
convenience of the user only.
---------------------------------------------------------------------------
(f) Proposed order. After reviewing the conclusions and
recommendations of the advisory review panel, the Commissioner of Food
and Drugs shall publish in the Federal Register a proposed order
containing:
(1) A statement designating the biological products in the category
under review that are determined by the Commissioner of Food and Drugs
to be safe and effective and not misbranded. This statement may include
any condition relating to active components, labeling, tests required
prior to release of lots, product standards, or other conditions
necessary or appropriate for their safety and effectiveness, and may
propose corresponding amendments in other regulations under this
subchapter F.
(2) A statement designating the biological products in the category
under review that are determined by the Commissioner of Food and Drugs
to be unsafe or ineffective, or to be misbranded, together with the
reasons therefor. All licenses for such products shall be proposed to be
revoked.
(3) A statement designating the biological products not included in
either of the above two statements on the
[[Page 35]]
basis of the Commissioner of Food and Drugs determination that the
available data are insufficient to classify such biological products
under either paragraph (f) (1) or (2) of this section. Licenses for such
products may be proposed to be revoked or to remain in effect on an
interim basis. Where the Commissioner determines that the potential
benefits outweigh the potential risks, the proposed order shall provide
that the biologics license for any biological product, falling within
this paragraph, will not be revoked but will remain in effect on an
interim basis while the data necessary to support its continued
marketing are being obtained for evaluation by the Food and Drug
Administration. The tests necessary to resolve whatever safety or
effectiveness questions exist shall be described. \2\
---------------------------------------------------------------------------
\2\ As of November 4, 1982, the provisions under paragraphs (e)(3)
and (f)(3) of this section for the interim marketing of certain
biological products pending completion of additional studies have been
superseded by the review and reclassification procedures under Sec.
601.26 of this chapter. The superseded text is included for the
convenience of the user only.
---------------------------------------------------------------------------
(4) The full report or reports of the panel to the Commissioner of
Food and Drugs.
The summary minutes of the panel meeting or meetings shall be made
available to interested persons upon request. Any interested person may
within 90 days after publication of the proposed order in the Federal
Register, file with the Hearing Clerk of the Food and Drug
Administration written comments in quintuplicate. Comments may be
accompanied by a memorandum or brief in support thereof. All comments
may be reviewed at the office of the Division of Dockets Management
during regular working hours, Monday through Friday.
(g) Final order. After reviewing the comments, the Commissioner of
Food and Drugs shall publish in the Federal Register a final order on
the matters covered in the proposed order. The final order shall become
effective as specified in the order.
(h) [Reserved]
(i) Court Appeal. The final order(s) published pursuant to paragraph
(g) of this section, and any notice published pursuant to paragraph (h)
of this section, constitute final agency action from which appeal lies
to the courts. The Food and Drug Administration will request
consolidation of all appeals in a single court. Upon court appeal, the
Commissioner of Food and Drugs may, at his discretion, stay the
effective date for part or all of the final order or notice, pending
appeal and final court adjudication.
[38 FR 32052, Nov. 20, 1973, as amended at 39 FR 11535, Mar. 29, 1974;
40 FR 13498, Mar. 27, 1975; 43 FR 44838, Sept. 29, 1978; 47 FR 44071,
Oct. 5, 1982; 47 FR 50211, Nov. 5, 1982; 51 FR 15607, Apr. 25, 1986; 55
FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997; 64 FR 56452, Oct.
20, 1999]
Sec. 601.26 Reclassification procedures to determine that licensed
biological products are safe, effective, and not misbranded under prescribed,
recommended, or suggested conditions of use.
This regulation establishes procedures for the reclassification of
all biological products that have been classified into Category IIIA. A
Category IIIA biological product is one for which an advisory review
panel has recommended under Sec. 601.25(e)(3), the Commissioner of Food
and Drugs (Commissioner) has proposed under Sec. 601.25(f)(3), or the
Commissioner has finally decided under Sec. 601.25(g) that available
data are insufficient to determine whether the product license should be
revoked or affirmed and which may be marketed pending the completion of
further testing. All of these Category IIIA products will either be
reclassified into Category I (safe, effective, and not misbranded) or
Category II (unsafe, ineffective, or misbranded) in accordance with the
procedures set forth below.
(a) Advisory review panels. The Commissioner will appoint advisory
review panels and use existing advisory review panels to (1) evaluate
the safety and effectiveness of all Category IIIA biological products;
(2) review the labeling of such products; and (3) advise the
Commissioner on which Category IIIA biological products are safe,
effective, and not misbranded. These advisory review panels will be
established in accordance with procedures set forth in Sec. 601.25(a).
(b) Deliberations of advisory review panels. The deliberations of
advisory
[[Page 36]]
review panels will be conducted in accordance with Sec. 601.25(d).
(c) Advisory review panel report to the Commissioner. An advisory
review panel shall submit to the Commissioner a report containing the
panel's conclusions and recommendations with respect to the biological
products falling within the category of products reviewed by the panel.
The panel report shall include:
(1) A statement designating the biological products in the category
under review in accordance with either Sec. 601.25(e)(1) or Sec.
601.25(e)(2).
(2) A statement identifying those biological products designated
under Sec. 601.25(e)(2) that the panel recommends should be designated
as safe and presumptively effective and should remain on the market
pending completion of further testing because there is a compelling
medical need and no suitable alternative therapeutic, prophylactic, or
diagnostic agent that is available in sufficient quantities to meet
current medical needs. For the products or categories of products so
recommended, the report shall include:
(i) A description and evaluation of the available evidence
concerning effectiveness and an explanation why the evidence shows that
the product has any benefit; and
(ii) A description of the alternative therapeutic, prophylactic, or
diagnostic agents considered and a statement of why such alternatives
are not suitable. In making this recommendation the panel shall also
take into account the seriousness of the condition intended to be
treated, prevented, or diagnosed by the product, the risks involved in
the continued use of the product, and the likelihood that, based upon
existing data, the effectiveness of the product can eventually be
established by further testing and new test development. The report
shall also recommend with as much specificity as possible the type of
further testing required and the time period within which it might
reasonably be concluded.
(d) Proposed order. After reviewing the conclusions and
recommendations of the advisory review panels, the Commissioner shall
publish in the Federal Register a proposed order containing:
(1) A statement designating the biological products in the category
under review in accordance with either Sec. 601.25(e)(1) or
601.25(e)(2);
(2) A notice of availability of the full panel report or reports.
The full panel report or reports shall be made publicly available at the
time of publication of the proposed order.
(3) A proposal to accept or reject the findings of the advisory
review panel required by Sec. 601.26(c)(2)(i) and (ii).
(4) A statement identifying those biological products that the
Commissioner proposes should be designated as safe and presumptively
effective under Sec. 601.26(c)(2) and should be permitted to remain on
the market pending completion of further testing because there is a
compelling medical need and no suitable alternative therapeutic,
prophylactic, or diagnostic agent for the product that is available in
sufficient quantities to meet current medical needs. In making this
proposal, the Commissioner shall take into account the seriousness of
the condition to be treated, prevented, or diagnosed by the product, the
risks involved in the continued use of the product, and the likelihood
that, based upon existing data, the effectiveness of the product can
eventually be established by further testing.
(e) Final order. After reviewing the comments on the proposed order,
the Commissioner shall publish in the Federal Register a final order on
the matters covered in the proposed order. Where the Commissioner
determines that there is a compelling medical need and no suitable
alternative therapeutic, prophylactic, or diagnostic agent for any
biological product that is available in sufficient quantities to meet
current medical needs, the final order shall provide that the biologics
license application for that biological product will not be revoked, but
will remain in effect on an interim basis while the data necessary to
support its continued marketing are being obtained for evaluation by the
Food and Drug Administration. The final order shall describe the tests
necessary to resolve whatever effectiveness questions exist.
(f) Additional studies and labeling. (1) Within 60 days following
publication of
[[Page 37]]
the final order, each licensed manufacturer for a biological product
designated as requiring further study to justify continued marketing on
an interim basis, under paragraph (e) of this section, shall submit to
the Commissioner a written statement intended to show that studies
adequate and appropriate to resolve the questions raised about the
product have been undertaken. The Federal Government may undertake the
studies. Any study involving a clinical investigation that involves
human subjects shall be conducted in compliance with the requirements
for informed consent under part 50 of this chapter. Such a study is also
subject to the requirements for institutional review under part 56 of
this chapter unless exempt under Sec. 56.104 or Sec. 56.105. The
Commissioner may extend this 60-day period if necessary, either to
review and act on proposed protocols or upon indication from the
licensed manufacturer that the studies will commence at a specified
reasonable time. If no such commitment is made, or adequate and
appropriate studies are not undertaken, the biologics license or
licenses shall be revoked.
(2) A progress report shall be filed on the studies by January 1 and
July 1 until completion. If the progress report is inadequate or if the
Commissioner concludes that the studies are not being pursued promptly
and diligently, or if interim results indicate the product is not a
medical necessity, the biologics license or licenses shall be revoked.
(3) Promptly upon completion of the studies undertaken on the
product, the Commissioner will review all available data and will either
retain or revoke the biologics license or licenses involved. In making
this review the Commissioner may again consult the advisory review panel
which prepared the report on the product, or other advisory committees,
professional organizations, or experts. The Commissioner shall take such
action by notice published in the Federal Register.
(4) Labeling and promotional material for those biological products
requiring additional studies shall bear a box statement in the following
format:
Based on a review by the (insert name of appropriate advisory review
panel) and other information, the Food and Drug Administration has
directed that further investigation be conducted before this product is
conclusively determined to be effective for labeled indication(s).
(5) A written informed consent shall be obtained from participants
in any additional studies required under paragraph (f)(1) of this
section, explaining the nature of the product and the investigation. The
explanation shall consist of such disclosure and be made so that
intelligent and informed consent be given and that a clear opportunity
to refuse is presented.
(g) Court appeal. The final order(s) published pursuant to paragraph
(e) of this section constitute final agency action from which appeal
lies to the courts. The Food and Drug Administration will request
consolidation of all appeals in a single court. Upon court appeal, the
Commissioner of Food and Drugs may, at the Commissioner's discretion,
stay the effective date for part or all of the final order or notice,
pending appeal and final court adjudication.
(h) [Reserved]
(i) Institutional review and informed consent. Information and data
submitted under this section after July 27, 1981, shall include
statements regarding each clinical investigation involving human
subjects, that it was conducted in compliance with the requirements for
informed consent under part 50 of this chapter. Such a study is also
subject to the requirements for institutional review under part 56 of
this chapter, unless exempt under Sec. 56.104 or Sec. 56.105.
[47 FR 44071, Oct. 5, 1982, as amended at 64 FR 56452, Oct. 20, 1999]
Sec. 601.27 Pediatric studies.
(a) Required assessment. Except as provided in paragraphs (b), (c),
and (d) of this section, each application for a new active ingredient,
new indication, new dosage form, new dosing regimen, or new route of
administration shall contain data that are adequate to assess the safety
and effectiveness of the product for the claimed indications in all
relevant pediatric subpopulations, and to support dosing and
administration for each pediatric subpopulation for which the product is
safe and effective. Where the course of the disease
[[Page 38]]
and the effects of the product are similar in adults and pediatric
patients, FDA may conclude that pediatric effectiveness can be
extrapolated from adequate and well-controlled effectiveness studies in
adults, usually supplemented with other information in pediatric
patients, such as pharmacokinetic studies. In addition, studies may not
be needed in each pediatric age group, if data from one age group can be
extrapolated to another. Assessments required under this section for a
product that represents a meaningful therapeutic benefit over existing
treatments must be carried out using appropriate formulations for the
age group(s) for which the assessment is required.
(b) Deferred submission. (1) FDA may, on its own initiative or at
the request of an applicant, defer submission of some or all assessments
of safety and effectiveness described in paragraph (a) of this section
until after licensing of the product for use in adults. Deferral may be
granted if, among other reasons, the product is ready for approval in
adults before studies in pediatric patients are complete, pediatric
studies should be delayed until additional safety or effectiveness data
have been collected. If an applicant requests deferred submission, the
request must provide an adequate justification for delaying pediatric
studies, a description of the planned or ongoing studies, and evidence
that the studies are being or will be conducted with due diligence and
at the earliest possible time.
(2) If FDA determines that there is an adequate justification for
temporarily delaying the submission of assessments of pediatric safety
and effectiveness, the product may be licensed for use in adults subject
to the requirement that the applicant submit the required assessments
within a specified time.
(c) Waivers--(1) General. FDA may grant a full or partial waiver of
the requirements of paragraph (a) of this section on its own initiative
or at the request of an applicant. A request for a waiver must provide
an adequate justification.
(2) Full waiver. An applicant may request a waiver of the
requirements of paragraph (a) of this section if the applicant certifies
that:
(i) The product does not represent a meaningful therapeutic benefit
over existing therapies for pediatric patients and is not likely to be
used in a substantial number of pediatric patients;
(ii) Necessary studies are impossible or highly impractical because,
e.g., the number of such patients is so small or geographically
dispersed; or
(iii) There is evidence strongly suggesting that the product would
be ineffective or unsafe in all pediatric age groups.
(3) Partial waiver. An applicant may request a waiver of the
requirements of paragraph (a) of this section with respect to a
specified pediatric age group, if the applicant certifies that:
(i) The product does not represent a meaningful therapeutic benefit
over existing therapies for pediatric patients in that age group, and is
not likely to be used in a substantial number of patients in that age
group;
(ii) Necessary studies are impossible or highly impractical because,
e.g., the number of patients in that age group is so small or
geographically dispersed;
(iii) There is evidence strongly suggesting that the product would
be ineffective or unsafe in that age group; or
(iv) The applicant can demonstrate that reasonable attempts to
produce a pediatric formulation necessary for that age group have
failed.
(4) FDA action on waiver. FDA shall grant a full or partial waiver,
as appropriate, if the agency finds that there is a reasonable basis on
which to conclude that one or more of the grounds for waiver specified
in paragraphs (c)(2) or (c)(3) of this section have been met. If a
waiver is granted on the ground that it is not possible to develop a
pediatric formulation, the waiver will cover only those pediatric age
groups requiring that formulation. If a waiver is granted because there
is evidence that the product would be ineffective or unsafe in pediatric
populations, this information will be included in the product's
labeling.
(5) Definition of ``meaningful therapeutic benefit''. For purposes
of this section, a product will be considered to offer a meaningful
therapeutic benefit over existing therapies if FDA estimates that:
[[Page 39]]
(i) If approved, the product would represent a significant
improvement in the treatment, diagnosis, or prevention of a disease,
compared to marketed products adequately labeled for that use in the
relevant pediatric population. Examples of how improvement might be
demonstrated include, e.g., evidence of increased effectiveness in
treatment, prevention, or diagnosis of disease; elimination or
substantial reduction of a treatment-limiting drug reaction; documented
enhancement of compliance; or evidence of safety and effectiveness in a
new subpopulation; or
(ii) The product is in a class of products or for an indication for
which there is a need for additional therapeutic options.
(d) Exemption for orphan drugs. This section does not apply to any
product for an indication or indications for which orphan designation
has been granted under part 316, subpart C, of this chapter.
[63 FR 66671, Dec. 2, 1998]
Sec. 601.28 Annual reports of postmarketing pediatric studies.
Sponsors of licensed biological products shall submit the following
information each year within 60 days of the anniversary date of approval
of each product under the license to the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research (see mailing addresses in Sec. 600.2 of this chapter):
(a) Summary. A brief summary stating whether labeling supplements
for pediatric use have been submitted and whether new studies in the
pediatric population to support appropriate labeling for the pediatric
population have been initiated. Where possible, an estimate of patient
exposure to the drug product, with special reference to the pediatric
population (neonates, infants, children, and adolescents) shall be
provided, including dosage form.
(b) Clinical data. Analysis of available safety and efficacy data in
the pediatric population and changes proposed in the labeling based on
this information. An assessment of data needed to ensure appropriate
labeling for the pediatric population shall be included.
(c) Status reports. A statement on the current status of any
postmarketing studies in the pediatric population performed by, or on
behalf of, the applicant. The statement shall include whether
postmarketing clinical studies in pediatric populations were required or
agreed to, and, if so, the status of these studies shall be reported to
FDA in annual progress reports of postmarketing studies under Sec.
601.70 rather than under this section.
[65 FR 59718, Oct. 6, 2000, as amended at 65 FR 64618, Oct. 30, 2000; 70
FR 14984, Mar. 24, 2005]
Sec. 601.29 Guidance documents.
(a) FDA has made available guidance documents under Sec. 10.115 of
this chapter to help you comply with certain requirements of this part.
(b) The Center for Biologics Evaluation and Research (CBER)
maintains a list of guidance documents that apply to the center's
regulations. The lists are maintained on the Internet and are published
annually in the Federal Register. You may request a copy of the CBER
list from the Office of Communication, Training, and Manufacturers
Assistance (HFM-40), Center for Biologics Evaluation and Research, Food
and Drug Administration (see mailing addresses in Sec. 600.2 of this
chapter).
[65 FR 56480, Sept. 19, 2000, as amended at 70 FR 14984, Mar. 24, 2005]
Subpart D_Diagnostic Radiopharmaceuticals
Source: 64 FR 26668, May 17, 1999, unless otherwise noted.
Sec. 601.30 Scope.
This subpart applies to radiopharmaceuticals intended for in vivo
administration for diagnostic and monitoring use. It does not apply to
radiopharmaceuticals intended for therapeutic purposes. In situations
where a particular radiopharmaceutical is proposed for both diagnostic
and therapeutic uses, the radiopharmaceutical must be evaluated taking
into account each intended use.
[[Page 40]]
Sec. 601.31 Definition.
For purposes of this part,diagnostic radiopharmaceutical means:
(a) An article that is intended for use in the diagnosis or
monitoring of a disease or a manifestation of a disease in humans and
that exhibits spontaneous disintegration of unstable nuclei with the
emission of nuclear particles or photons; or
(b) Any nonradioactive reagent kit or nuclide generator that is
intended to be used in the preparation of such article as defined in
paragraph (a) of this section.
Sec. 601.32 General factors relevant to safety and effectiveness.
FDA's determination of the safety and effectiveness of a diagnostic
radiopharmaceutical includes consideration of the following:
(a) The proposed use of the diagnostic radiopharmaceutical in the
practice of medicine;
(b) The pharmacological and toxicological activity of the diagnostic
radiopharmaceutical (including any carrier or ligand component of the
diagnostic radiopharmaceutical); and
(c) The estimated absorbed radiation dose of the diagnostic
radiopharmaceutical.
Sec. 601.33 Indications.
(a) For diagnostic radiopharmaceuticals, the categories of proposed
indications for use include, but are not limited to, the following:
(1) Structure delineation;
(2) Functional, physiological, or biochemical assessment;
(3) Disease or pathology detection or assessment; and
(4) Diagnostic or therapeutic patient management.
(b) Where a diagnostic radiopharmaceutical is not intended to
provide disease-specific information, the proposed indications for use
may refer to a biochemical, physiological, anatomical, or pathological
process or to more than one disease or condition.
Sec. 601.34 Evaluation of effectiveness.
(a) The effectiveness of a diagnostic radiopharmaceutical is
assessed by evaluating its ability to provide useful clinical
information related to its proposed indications for use. The method of
this evaluation varies depending upon the proposed indication(s) and may
use one or more of the following criteria:
(1) The claim of structure delineation is established by
demonstrating in a defined clinical setting the ability to locate
anatomical structures and to characterize their anatomy.
(2) The claim of functional, physiological, or biochemical
assessment is established by demonstrating in a defined clinical setting
reliable measurement of function(s) or physiological, biochemical, or
molecular process(es).
(3) The claim of disease or pathology detection or assessment is
established by demonstrating in a defined clinical setting that the
diagnostic radiopharmaceutical has sufficient accuracy in identifying or
characterizing the disease or pathology.
(4) The claim of diagnostic or therapeutic patient management is
established by demonstrating in a defined clinical setting that the test
is useful in diagnostic or therapeutic patient management.
(5) For a claim that does not fall within the indication categories
identified in Sec. 601.33, the applicant or sponsor should consult FDA
on how to establish the effectiveness of the diagnostic
radiopharmaceutical for the claim.
(b) The accuracy and usefulness of the diagnostic information is
determined by comparison with a reliable assessment of actual clinical
status. A reliable assessment of actual clinical status may be provided
by a diagnostic standard or standards of demonstrated accuracy. In the
absence of such diagnostic standard(s), the actual clinical status must
be established in another manner, e.g., patient followup.
Sec. 601.35 Evaluation of safety.
(a) Factors considered in the safety assessment of a diagnostic
radiopharmaceutical include, among others, the following:
(1) The radiation dose;
(2) The pharmacology and toxicology of the radiopharmaceutical,
including any radionuclide, carrier, or ligand;
(3) The risks of an incorrect diagnostic determination;
[[Page 41]]
(4) The adverse reaction profile of the drug;
(5) Results of human experience with the radiopharmaceutical for
other uses; and
(6) Results of any previous human experience with the carrier or
ligand of the radiopharmaceutical when the same chemical entity as the
carrier or ligand has been used in a previously studied product.
(b) The assessment of the adverse reaction profile includes, but is
not limited to, an evaluation of the potential of the diagnostic
radiopharmaceutical, including the carrier or ligand, to elicit the
following:
(1) Allergic or hypersensitivity responses,
(2) Immunologic responses,
(3) Changes in the physiologic or biochemical function of the target
and nontarget tissues, and
(4) Clinically detectable signs or symptoms.
(c)(1) To establish the safety of a diagnostic radiopharmaceutical,
FDA may require, among other information, the following types of data:
(A) Pharmacology data,
(B) Toxicology data,
(C) Clinical adverse event data, and
(D) Radiation safety assessment.
(2) The amount of new safety data required will depend on the
characteristics of the product and available information regarding the
safety of the diagnostic radiopharmaceutical, and its carrier or ligand,
obtained from other studies and uses. Such information may include, but
is not limited to, the dose, route of administration, frequency of use,
half-life of the ligand or carrier, half-life of the radionuclide, and
results of clinical and preclinical studies. FDA will establish
categories of diagnostic radiopharmaceuticals based on defined
characteristics relevant to risk and will specify the amount and type of
safety data that are appropriate for each category (e.g., required
safety data may be limited for diagnostic radiopharmaceuticals with a
well established, low-risk profile). Upon reviewing the relevant product
characteristics and safety information, FDA will place each diagnostic
radiopharmaceutical into the appropriate safety risk category.
(d) Radiation safety assessment. The radiation safety assessment
must establish the radiation dose of a diagnostic radiopharmaceutical by
radiation dosimetry evaluations in humans and appropriate animal models.
The maximum tolerated dose need not be established.
Subpart E_Accelerated Approval of Biological Products for Serious or
Life-Threatening Illnesses
Source: 57 FR 58959, Dec. 11, 1992, unless otherwise noted.
Sec. 601.40 Scope.
This subpart applies to certain biological products that have been
studied for their safety and effectiveness in treating serious or life-
threatening illnesses and that provide meaningful therapeutic benefit to
patients over existing treatments (e.g., ability to treat patients
unresponsive to, or intolerant of, available therapy, or improved
patient response over available therapy).
Sec. 601.41 Approval based on a surrogate endpoint or on an effect on a
clinical endpoint other than survival or irreversible morbidity.
FDA may grant marketing approval for a biological product on the
basis of adequate and well-controlled clinical trials establishing that
the biological product has an effect on a surrogate endpoint that is
reasonably likely, based on epidemiologic, therapeutic,
pathophysiologic, or other evidence, to predict clinical benefit or on
the basis of an effect on a clinical endpoint other than survival or
irreversible morbidity. Approval under this section will be subject to
the requirement that the applicant study the biological product further,
to verify and describe its clinical benefit, where there is uncertainty
as to the relation of the surrogate endpoint to clinical benefit, or of
the observed clinical benefit to ultimate outcome. Postmarketing studies
would usually be studies already underway. When required to be
conducted, such studies must also be adequate and well-controlled. The
applicant shall carry out any such studies with due diligence.
[[Page 42]]
Sec. 601.42 Approval with restrictions to assure safe use.
(a) If FDA concludes that a biological product shown to be effective
can be safely used only if distribution or use is restricted, FDA will
require such postmarketing restrictions as are needed to assure safe use
of the biological product, such as:
(1) Distribution restricted to certain facilities or physicians with
special training or experience; or
(2) Distribution conditioned on the performance of specified medical
procedures.
(b) The limitations imposed will be commensurate with the specific
safety concerns presented by the biological product.
Sec. 601.43 Withdrawal procedures.
(a) For biological products approved under Sec. 601.41 or Sec.
601.42, FDA may withdraw approval, following a hearing as provided in
part 15 of this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the required postmarketing study
with due diligence;
(3) Use after marketing demonstrates that postmarketing restrictions
are inadequate to ensure safe use of the biological product;
(4) The applicant fails to adhere to the postmarketing restrictions
agreed upon;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the biological product is not
shown to be safe or effective under its conditions of use.
(b) Notice of opportunity for a hearing. The Director of the Center
for Biologics Evaluation and Research or the Director of the Center for
Drug Evaluation and Research will give the applicant notice of an
opportunity for a hearing on the Center's proposal to withdraw the
approval of an application approved under Sec. 601.41 or Sec. 601.42.
The notice, which will ordinarily be a letter, will state generally the
reasons for the action and the proposed grounds for the order.
(c) Submission of data and information. (1) If the applicant fails
to file a written request for a hearing within 15 days of receipt of the
notice, the applicant waives the opportunity for a hearing.
(2) If the applicant files a timely request for a hearing, the
agency will publish a notice of hearing in the Federal Register in
accordance with Sec. Sec. 12.32(e) and 15.20 of this chapter.
(3) An applicant who requests a hearing under this section must,
within 30 days of receipt of the notice of opportunity for a hearing,
submit the data and information upon which the applicant intends to rely
at the hearing.
(d) Separation of functions. Separation of functions (as specified
in Sec. 10.55 of this chapter) will not apply at any point in
withdrawal proceedings under this section.
(e) Procedures for hearings. Hearings held under this section will
be conducted in accordance with the provisions of part 15 of this
chapter, with the following modifications:
(1) An advisory committee duly constituted under part 14 of this
chapter will be present at the hearing. The committee will be asked to
review the issues involved and to provide advice and recommendations to
the Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to
three representatives of the applicant, and up to three representatives
of the Center may question any person during or at the conclusion of the
person's presentation. No other person attending the hearing may
question a person making a presentation. The presiding officer may, as a
matter of discretion, permit questions to be submitted to the presiding
officer for response by a person making a presentation.
(f) Judicial review. The Commissioner's decision constitutes final
agency action from which the applicant may petition for judicial review.
Before requesting an order from a court for a stay of action pending
review, an applicant must first submit a petition for a stay of action
under Sec. 10.35 of this chapter.
[57 FR 58959, Dec. 11, 1992, as amended at 68 FR 34797, June 11, 2003;
70 FR 14984, Mar. 24, 2005]
[[Page 43]]
Sec. 601.44 Postmarketing safety reporting.
Biological products approved under this program are subject to the
postmarketing recordkeeping and safety reporting applicable to all
approved biological products.
Sec. 601.45 Promotional materials.
For biological products being considered for approval under this
subpart, unless otherwise informed by the agency, applicants must submit
to the agency for consideration during the preapproval review period
copies of all promotional materials, including promotional labeling as
well as advertisements, intended for dissemination or publication within
120 days following marketing approval. After 120 days following
marketing approval, unless otherwise informed by the agency, the
applicant must submit promotional materials at least 30 days prior to
the intended time of initial dissemination of the labeling or initial
publication of the advertisement.
Sec. 601.46 Termination of requirements.
If FDA determines after approval that the requirements established
in Sec. 601.42, Sec. 601.43, or Sec. 601.45 are no longer necessary
for the safe and effective use of a biological product, it will so
notify the applicant. Ordinarily, for biological products approved under
Sec. 601.41, these requirements will no longer apply when FDA
determines that the required postmarketing study verifies and describes
the biological product's clinical benefit and the biological product
would be appropriate for approval under traditional procedures. For
biological products approved under Sec. 601.42, the restrictions would
no longer apply when FDA determines that safe use of the biological
product can be assured through appropriate labeling. FDA also retains
the discretion to remove specific postapproval requirements upon review
of a petition submitted by the sponsor in accordance with Sec. 10.30.
Subpart F_Confidentiality of Information
Sec. 601.50 Confidentiality of data and information in an investigational
new drug notice for a biological product.
(a) The existence of an IND notice for a biological product will not
be disclosed by the Food and Drug Administration unless it has
previously been publicly disclosed or acknowledged.
(b) The availability for public disclosure of all data and
information in an IND file for a biological product shall be handled in
accordance with the provisions established in Sec. 601.51.
(c) Notwithstanding the provisions of Sec. 601.51, the Food and
Drug Administration shall disclose upon request to an individual on whom
an investigational biological product has been used a copy of any
adverse reaction report relating to such use.
[39 FR 44656, Dec. 24, 1974]
Sec. 601.51 Confidentiality of data and information in applications for
biologics licenses.
(a) For purposes of this section the biological product file
includes all data and information submitted with or incorporated by
reference in any application for a biologics license, IND's incorporated
into any such application, master files, and other related submissions.
The availability for public disclosure of any record in the biological
product file shall be handled in accordance with the provisions of this
section.
(b) The existence of a biological product file will not be disclosed
by the Food and Drug Administration before a biologics license
application has been approved unless it has previously been publicly
disclosed or acknowledged. The Food and Drug Administration will
maintain a list available for public disclosure of biological products
for which a license application has been approved.
(c) If the existence of a biological product file has not been
publicly disclosed or acknowledged, no data or information in the
biological product file is available for public disclosure.
(d)(1) If the existence of a biological product file has been
publicly disclosed or acknowledged before a license has
[[Page 44]]
been issued, no data or information contained in the file is available
for public disclosure before such license is issued, but the
Commissioner may, in his discretion, disclose a summary of such selected
portions of the safety and effectiveness data as are appropriate for
public consideration of a specific pending issue, e.g., at an open
session of a Food and Drug Administration advisory committee or pursuant
to an exchange of important regulatory information with a foreign
government.
(2) Notwithstanding paragraph (d)(1) of this section, FDA will make
available to the public upon request the information in the IND that was
required to be filed in Docket Number 95S-0158 in the Division of
Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852, for investigations involving an
exception from informed consent under Sec. 50.24 of this chapter.
Persons wishing to request this information shall submit a request under
the Freedom of Information Act.
(e) After a license has been issued, the following data and
information in the biological product file are immediately available for
public disclosure unless extraordinary circumstances are shown:
(1) All safety and effectiveness data and information.
(2) A protocol for a test or study, unless it is shown to fall
within the exemption established for trade secrets and confidential
commercial or financial information in Sec. 20.61 of this chapter.
(3) Adverse reaction reports, product experience reports, consumer
complaints, and other similar data and information, after deletion of:
(i) Names and any information that would identify the person using
the product.
(ii) Names and any information that would identify any third party
involved with the report, such as a physician or hospital or other
institution.
(4) A list of all active ingredients and any inactive ingredients
previously disclosed to the public, as defined in Sec. 20.81 of this
chapter.
(5) An assay method or other analytical method, unless it serves no
regulatory or compliance purpose and it is shown to fall within the
exemption established in Sec. 20.61 of this chapter.
(6) All correspondence and written summaries of oral discussions
relating to the biological product file, in accordance with the
provisions of part 20 of this chapter.
(7) All records showing the manufacturer's testing of a particular
lot, after deletion of data or information that would show the volume of
the drug produced, manufacturing procedures and controls, yield from raw
materials, costs, or other material falling within Sec. 20.61 of this
chapter.
(8) All records showing the testing of and action on a particular
lot by the Food and Drug Administration.
(f) The following data and information in a biological product file
are not available for public disclosure unless they have been previously
disclosed to the public as defined in Sec. 20.81 of this chapter or
they relate to a product or ingredient that has been abandoned and they
no longer represent a trade secret or confidential commercial or
financial information as defined in Sec. 20.61 of this chapter:
(1) Manufacturing methods or processes, including quality control
procedures.
(2) Production, sales, distribution, and similar data and
information, except that any compilation of such data and information
aggregated and prepared in a way that does not reveal data or
information which is not available for public disclosure under this
provision is available for public disclosure.
(3) Quantitative or semiquantitative formulas.
(g) For purposes of this regulation, safety and effectiveness data
include all studies and tests of a biological product on animals and
humans and all studies and tests on the drug for identity, stability,
purity, potency, and bioavailability.
[39 FR 44656, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977;
49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 51530, Oct.
2, 1996; 64 FR 56452, Oct. 20, 1999; 68 FR 24879, May 9, 2003; 69 FR
13717, Mar. 24, 2004; 70 FR 14984, Mar. 24, 2005]
[[Page 45]]
Subpart G_Postmarketing Studies
Source: 65 FR 64618, Oct. 30, 2000, unless otherwise noted.
Sec. 601.70 Annual progress reports of postmarketing studies.
(a) General requirements. This section applies to all required
postmarketing studies (e.g., accelerated approval clinical benefit
studies, pediatric studies) and postmarketing studies that an applicant
has committed, in writing, to conduct either at the time of approval of
an application or a supplement to an application, or after approval of
an application or a supplement. Postmarketing studies within the meaning
of this section are those that concern:
(1) Clinical safety;
(2) Clinical efficacy;
(3) Clinical pharmacology; and
(4) Nonclinical toxicology.
(b)What to report. Each applicant of a licensed biological product
shall submit a report to FDA on the status of postmarketing studies for
each approved product application. The status of these postmarketing
studies shall be reported annually until FDA notifies the applicant, in
writing, that the agency concurs with the applicant's determination that
the study commitment has been fulfilled, or that the study is either no
longer feasible or would no longer provide useful information. Each
annual progress report shall be accompanied by a completed transmittal
Form FDA-2252, and shall include all the information required under this
section that the applicant received or otherwise obtained during the
annual reporting interval which ends on the U.S. anniversary date. The
report must provide the following information for each postmarketing
study:
(1) Applicant's name.
(2) Product name. Include the approved product's proper name and the
proprietary name, if any.
(3) Biologics license application (BLA) and supplement number.
(4) Date of U.S. approval of BLA.
(5) Date of postmarketing study commitment.
(6) Description of postmarketing study commitment. The description
must include sufficient information to uniquely describe the study. This
information may include the purpose of the study, the type of study, the
patient population addressed by the study and the indication(s) and
dosage(s) that are to be studied.
(7) Schedule for completion and reporting of the postmarketing study
commitment. The schedule should include the actual or projected dates
for submission of the study protocol to FDA, completion of patient
accrual or initiation of an animal study, completion of the study,
submission of the final study report to FDA, and any additional
milestones or submissions for which projected dates were specified as
part of the commitment. In addition, it should include a revised
schedule, as appropriate. If the schedule has been previously revised,
provide both the original schedule and the most recent, previously
submitted revision.
(8) Current status of the postmarketing study commitment. The status
of each postmarketing study should be categorized using one of the
following terms that describes the study's status on the anniversary
date of U.S. approval of the application or other agreed upon date:
(i) Pending. The study has not been initiated, but does not meet the
criterion for delayed.
(ii) Ongoing. The study is proceeding according to or ahead of the
original schedule described under paragraph (b)(7) of this section.
(iii) Delayed. The study is behind the original schedule described
under paragraph (b)(7) of this section.
(iv) Terminated. The study was ended before completion but a final
study report has not been submitted to FDA.
(v) Submitted. The study has been completed or terminated and a
final study report has been submitted to FDA.
(9) Explanation of the study's status. Provide a brief description
of the status of the study, including the patient accrual rate
(expressed by providing the number of patients or subjects enrolled to
date, and the total planned enrollment), and an explanation of the
study's status identified under paragraph (b)(8) of this section. If the
study has been completed, include the date the study was completed and
the date
[[Page 46]]
the final study report was submitted to FDA, as applicable. Provide a
revised schedule, as well as the reason(s) for the revision, if the
schedule under paragraph (b)(7) of this section has changed since the
previous report.
(c) When to report. Annual progress reports for postmarketing study
commitments entered into by applicants shall be reported to FDA within
60 days of the anniversary date of the U.S. approval of the application
for the product.
(d) Where to report. Submit two copies of the annual progress report
of postmarketing studies to the Center for Biologics Evaluation and
Research or Center for Drug Evaluation and Research (see mailing
addresses in Sec. 600.2 of this chapter).
(e) Public disclosure of information. Except for the information
described in this paragraph, FDA may publicly disclose any information
concerning a postmarketing study, within the meaning of this section, if
the agency determines that the information is necessary to identify an
applicant or to establish the status of the study including the reasons,
if any, for failure to conduct, complete, and report the study. Under
this section, FDA will not publicly disclose trade secrets, as defined
in Sec. 20.61 of this chapter, or information, described in Sec. 20.63
of this chapter, the disclosure of which would constitute an unwarranted
invasion of personal privacy.
[65 FR 64618, Oct. 30, 2000, as amended at 70 FR 14984, Mar. 24, 2005]
Subpart H_Approval of Biological Products When Human Efficacy Studies
Are Not Ethical or Feasible
Source: 67 FR 37996, May 31, 2002, unless otherwise noted.
Sec. 601.90 Scope.
This subpart applies to certain biological products that have been
studied for their safety and efficacy in ameliorating or preventing
serious or life-threatening conditions caused by exposure to lethal or
permanently disabling toxic biological, chemical, radiological, or
nuclear substances. This subpart applies only to those biological
products for which: Definitive human efficacy studies cannot be
conducted because it would be unethical to deliberately expose healthy
human volunteers to a lethal or permanently disabling toxic biological,
chemical, radiological, or nuclear substance; and field trials to study
the product's efficacy after an accidental or hostile exposure have not
been feasible. This subpart does not apply to products that can be
approved based on efficacy standards described elsewhere in FDA's
regulations (e.g., accelerated approval based on surrogate markers or
clinical endpoints other than survival or irreversible morbidity), nor
does it address the safety evaluation for the products to which it does
apply.
Sec. 601.91 Approval based on evidence of effectiveness from studies in
animals.
(a) FDA may grant marketing approval for a biological product for
which safety has been established and for which the requirements of
Sec. 601.90 are met based on adequate and well-controlled animal
studies when the results of those animal studies establish that the
biological product is reasonably likely to produce clinical benefit in
humans. In assessing the sufficiency of animal data, the agency may take
into account other data, including human data, available to the agency.
FDA will rely on the evidence from studies in animals to provide
substantial evidence of the effectiveness of these products only when:
(1) There is a reasonably well-understood pathophysiological
mechanism of the toxicity of the substance and its prevention or
substantial reduction by the product;
(2) The effect is demonstrated in more than one animal species
expected to react with a response predictive for humans, unless the
effect is demonstrated in a single animal species that represents a
sufficiently well-characterized animal model for predicting the response
in humans;
(3) The animal study endpoint is clearly related to the desired
benefit in humans, generally the enhancement of survival or prevention
of major morbidity; and
[[Page 47]]
(4) The data or information on the kinetics and pharmacodynamics of
the product or other relevant data or information, in animals and
humans, allows selection of an effective dose in humans.
(b) Approval under this subpart will be subject to three
requirements:
(1) Postmarketing studies. The applicant must conduct postmarketing
studies, such as field studies, to verify and describe the biological
product's clinical benefit and to assess its safety when used as
indicated when such studies are feasible and ethical. Such postmarketing
studies would not be feasible until an exigency arises. When such
studies are feasible, the applicant must conduct such studies with due
diligence. Applicants must include as part of their application a plan
or approach to postmarketing study commitments in the event such studies
become ethical and feasible.
(2) Approval with restrictions to ensure safe use. If FDA concludes
that a biological product shown to be effective under this subpart can
be safely used only if distribution or use is restricted, FDA will
require such postmarketing restrictions as are needed to ensure safe use
of the biological product, commensurate with the specific safety
concerns presented by the biological product, such as:
(i) Distribution restricted to certain facilities or health care
practitioners with special training or experience;
(ii) Distribution conditioned on the performance of specified
medical procedures, including medical followup; and
(iii) Distribution conditioned on specified recordkeeping
requirements.
(3) Information to be provided to patient recipients. For biological
products or specific indications approved under this subpart, applicants
must prepare, as part of their proposed labeling, labeling to be
provided to patient recipients. The patient labeling must explain that,
for ethical or feasibility reasons, the biological product's approval
was based on efficacy studies conducted in animals alone and must give
the biological product's indication(s), directions for use (dosage and
administration), contraindications, a description of any reasonably
foreseeable risks, adverse reactions, anticipated benefits, drug
interactions, and any other relevant information required by FDA at the
time of approval. The patient labeling must be available with the
product to be provided to patients prior to administration or dispensing
of the biological product for the use approved under this subpart, if
possible.
Sec. 601.92 Withdrawal procedures.
(a) Reasons to withdraw approval. For biological products approved
under this subpart, FDA may withdraw approval, following a hearing as
provided in part 15 of this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the postmarketing study with due
diligence;
(3) Use after marketing demonstrates that postmarketing restrictions
are inadequate to ensure safe use of the biological product;
(4) The applicant fails to adhere to the postmarketing restrictions
applied at the time of approval under this subpart;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the biological product is not
shown to be safe or effective under its conditions of use.
(b) Notice of opportunity for a hearing. The Director of the Center
for Biologics Evaluation and Research or the Director of the Center for
Drug Evaluation and Research will give the applicant notice of an
opportunity for a hearing on the proposal to withdraw the approval of an
application approved under this subpart. The notice, which will
ordinarily be a letter, will state generally the reasons for the action
and the proposed grounds for the order.
(c) Submission of data and information. (1) If the applicant fails
to file a written request for a hearing within 15 days of receipt of the
notice, the applicant waives the opportunity for a hearing.
(2) If the applicant files a timely request for a hearing, the
agency will publish a notice of hearing in the Federal Register in
accordance with Sec. Sec. 12.32(e) and 15.20 of this chapter.
(3) An applicant who requests a hearing under this section must,
within 30
[[Page 48]]
days of receipt of the notice of opportunity for a hearing, submit the
data and information upon which the applicant intends to rely at the
hearing.
(d) Separation of functions. Separation of functions (as specified
in Sec. 10.55 of this chapter) will not apply at any point in
withdrawal proceedings under this section.
(e) Procedures for hearings. Hearings held under this section will
be conducted in accordance with the provisions of part 15 of this
chapter, with the following modifications:
(1) An advisory committee duly constituted under part 14 of this
chapter will be present at the hearing. The committee will be asked to
review the issues involved and to provide advice and recommendations to
the Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to
three representatives of the applicant, and up to three representatives
of CBER may question any person during or at the conclusion of the
person's presentation. No other person attending the hearing may
question a person making a presentation. The presiding officer may, as a
matter of discretion, permit questions to be submitted to the presiding
officer for response by a person making a presentation.
(f) Judicial review. The Commissioner of Food and Drugs' decision
constitutes final agency action from which the applicant may petition
for judicial review. Before requesting an order from a court for a stay
of action pending review, an applicant must first submit a petition for
a stay of action under Sec. 10.35 of this chapter.
[67 FR 37996, May 31, 2002, as amended at 70 FR 14984, Mar. 24, 2005]
Sec. 601.93 Postmarketing safety reporting.
Biological products approved under this subpart are subject to the
postmarketing recordkeeping and safety reporting applicable to all
approved biological products.
Sec. 601.94 Promotional materials.
For biological products being considered for approval under this
subpart, unless otherwise informed by the agency, applicants must submit
to the agency for consideration during the preapproval review period
copies of all promotional materials, including promotional labeling as
well as advertisements, intended for dissemination or publication within
120 days following marketing approval. After 120 days following
marketing approval, unless otherwise informed by the agency, the
applicant must submit promotional materials at least 30 days prior to
the intended time of initial dissemination of the labeling or initial
publication of the advertisement.
Sec. 601.95 Termination of requirements.
If FDA determines after approval under this subpart that the
requirements established in Sec. Sec. 601.91(b)(2), 601.92, and 601.93
are no longer necessary for the safe and effective use of a biological
product, FDA will so notify the applicant. Ordinarily, for biological
products approved under Sec. 601.91, these requirements will no longer
apply when FDA determines that the postmarketing study verifies and
describes the biological product's clinical benefit. For biological
products approved under Sec. 601.91, the restrictions would no longer
apply when FDA determines that safe use of the biological product can be
ensured through appropriate labeling. FDA also retains the discretion to
remove specific postapproval requirements upon review of a petition
submitted by the sponsor in accordance with Sec. 10.30 of this chapter.
PART 606_CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD COMPONENTS--
Table of Contents
Subpart A_General Provisions
Sec.
606.3 Definitions.
Subpart B_Organization and Personnel
606.20 Personnel.
Subpart C_Plant and Facilities
606.40 Facilities.
Subpart D_Equipment
606.60 Equipment.
[[Page 49]]
606.65 Supplies and reagents.
Subpart E [Reserved]
Subpart F_Production and Process Controls
606.100 Standard operating procedures.
606.110 Plateletpheresis, leukapheresis, and plasmapheresis.
Subpart G_Finished Product Control
606.120 Labeling, general requirements.
606.121 Container label.
606.122 Instruction circular.
Subpart H_Laboratory Controls
606.140 Laboratory controls.
606.151 Compatibility testing.
Subpart I_Records and Reports
606.160 Records.
606.165 Distribution and receipt; procedures and records.
606.170 Adverse reaction file.
606.171 Reporting of product deviations by licensed manufacturers,
unlicensed registered blood establishments, and transfusion
services.
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 374;
42 U.S.C. 216, 262, 263a, 264.
Source: 40 FR 53532, Nov. 18, 1975, unless otherwise noted.
Subpart A_General Provisions
Sec. 606.3 Definitions.
As used in this part:
(a) Blood means whole blood collected from a single donor and
processed either for transfusion or further manufacturing.
(b) Unit means the volume of blood or one of its components in a
suitable volume of anticoagulant obtained from a single collection of
blood from one donor.
(c) Component means that part of a single-donor's blood separated by
physical or mechanical means.
(d) Plasma for further manufacturing means that liquid portion of
blood separated and used as material to prepare another product.
(e) Plasmapheresis means the procedure in which blood is removed
from the donor, the plasma is separated from the formed elements and at
least the red blood cells are returned to the donor.
(f) Plateletpheresis means the procedure in which blood is removed
from a donor, a platelet concentrate is separated, and the remaining
formed elements are returned to the donor along with a portion of the
residual plasma.
(g) Leukapheresis means the procedure in which blood is removed from
the donor, a leukocyte concentrate is separated, and the remaining
formed elements and residual plasma are returned to the donor.
(h) Facilities means any area used for the collection, processing,
compatibility testing, storage or distribution of blood and blood
components.
(i) Processing means any procedure employed after collection, and
before or after compatibility testing of blood, and includes the
identification of a unit of donor blood, the preparation of components
from such unit of donor blood, serological testing, labeling and
associated recordkeeping.
(j) Compatibility testing means the procedures performed to
establish the matching of a donor's blood or blood components with that
of a potential recipient.
(k) Distributed means:
(1) The blood or blood components have left the control of the
licensed manufacturer, unlicensed registered blood establishment, or
transfusion service; or
(2) The licensed manufacturer has provided Source Plasma or any
other blood component for use in the manufacture of a licensed
biological product.
(l) Control means having responsibility for maintaining the
continued safety, purity, and potency of the product and for compliance
with applicable product and establishment standards, and for compliance
with current good manufacturing practices.
[40 FR 53532, Nov. 18, 1975, as amended at 64 FR 45370, Aug. 19, 1999;
65 FR 66635, Nov. 7, 2000; 66 FR 1835, Jan. 10, 2001; 66 FR 40889, Aug.
6, 2001; 72 FR 45886, Aug. 16, 2007]
Subpart B_Organization and Personnel
Sec. 606.20 Personnel.
(a) [Reserved]
(b) The personnel responsible for the collection, processing,
compatibility testing, storage or distribution of blood
[[Page 50]]
or blood components shall be adequate in number, educational background,
training and experience, including professional training as necessary,
or combination thereof, to assure competent performance of their
assigned functions, and to ensure that the final product has the safety,
purity, potency, identity and effectiveness it purports or is
represented to possess. All personnel shall have capabilities
commensurate with their assigned functions, a thorough understanding of
the procedures or control operations they perform, the necessary
training or experience, and adequate information concerning the
application of pertinent provisions of this part to their respective
functions.
(c) Persons whose presence can adversely affect the safety and
purity of the products shall be excluded from areas where the
collection, processing, compatibility testing, storage or distribution
of blood or blood components is conducted.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997]
Subpart C_Plant and Facilities
Sec. 606.40 Facilities.
Facilities shall be maintained in a clean and orderly manner, and
shall be of suitable size, construction and location to facilitate
adequate cleaning, maintenance and proper operations. The facilities
shall:
(a) Provide adequate space for the following when applicable:
(1) Private and accurate examinations of individuals to determine
their suitability as blood donors.
(2) The withdrawal of blood from donors with minimal risk of
contamination, or exposure to activities and equipment unrelated to
blood collection.
(3) The storage of blood or blood components pending completion of
tests.
(4) The quarantine storage of blood or blood components in a
designated location pending repetition of those tests that initially
gave questionable serological results.
(5) The storage of finished products prior to distribution.
(6) The quarantine storage, handling and disposition of products and
reagents not suitable for use.
(7) The orderly collection, processing, compatibility testing,
storage and distribution of blood and blood components to prevent
contamination.
(8) The adequate and proper performance of all steps in
plasmapheresis, plateletpheresis and leukapheresis procedures.
(9) The orderly conduction of all packaging, labeling and other
finishing operations.
(b) Provide adequate lighting, ventilation and screening of open
windows and doors.
(c) Provide adequate, clean, and convenient handwashing facilities
for personnel, and adequate, clean, and convenient toilet facilities for
donors and personnel. Drains shall be of adequate size and, where
connected directly to a sewer, shall be equipped with traps to prevent
back-siphonage.
(d) Provide for safe and sanitary disposal for the following:
(1) Trash and items used during the collection, processing and
compatibility testing of blood and blood components.
(2) Blood and blood components not suitable for use or distribution.
Subpart D_Equipment
Sec. 606.60 Equipment.
(a) Equipment used in the collection, processing, compatibility
testing, storage and distribution of blood and blood components shall be
maintained in a clean and orderly manner and located so as to facilitate
cleaning and maintenance. The equipment shall be observed, standardized
and calibrated on a regularly scheduled basis as prescribed in the
Standard Operating Procedures Manual and shall perform in the manner for
which it was designed so as to assure compliance with the official
requirements prescribed in this chapter for blood and blood products.
(b) Equipment that shall be observed, standardized and calibrated
with at least the following frequency, include but are not limited to:
[[Page 51]]
----------------------------------------------------------------------------------------------------------------
Equipment Performance check Frequency Frequency of calibration
----------------------------------------------------------------------------------------------------------------
Temperature recorder.............. Compare against Daily................ As necessary.
thermometer.
Refrigerated centrifuge........... Observe speed and Each day of use...... Do.
temperature.
Hematocrit centrifuge............. .......................... ..................... Standardize before
initial use, after
repairs or adjustments,
and annually. Timer
every 3 mo.
General lab centrifuge............ .......................... ..................... Tachometer every 6 mo.
Automated blood-typing machine.... Observe controls for Each day of use......
correct results.
Hemoglobinometer.................. Standardize against ......do.............
cyanmethemoglobin
standard.
Refractometer..................... Standardize against ......do.............
distilled water.
Blood container scale............. Standardize against ......do............. As necessary.
container of known weight.
Water bath........................ Observe temperature....... ......do............. Do.
Rh view box....................... ......do.................. ......do............. Do.
Autoclave......................... ......do.................. Each time of use..... Do.
Serologic rotators................ Observe controls for Each day of use...... Speed as necessary.
correct results.
Laboratory thermometers........... .......................... ..................... Before initial use.
Electronic thermometers........... .......................... ..................... Monthly.
Vacuum blood agitator............. Observe weight of the Each day of use...... Standardize with
first container of blood container of known mass
filled for correct or volume before initial
results. use, and after repairs
or adjustments.
----------------------------------------------------------------------------------------------------------------
(c) Equipment employed in the sterilization of materials used in
blood collection or for disposition of contaminated products shall be
designed, maintained and utilized to ensure the destruction of
contaminating microorganisms. The effectiveness of the sterilization
procedure shall be no less than that achieved by an attained temperature
of 121.5 [deg]C (251 [deg]F) maintained for 20 minutes by saturated
steam or by an attained temperature of 170 [deg]C (338 [deg]F)
maintained for 2 hours with dry heat.
[40 FR 53532, Nov. 18, 1975; 40 FR 55849, Dec. 2, 1975, as amended at 45
FR 9261, Feb. 12, 1980; 57 FR 11263, Apr. 2, 1992; 57 FR 12862, Apr. 13,
1992]
Sec. 606.65 Supplies and reagents.
All supplies and reagents used in the collection, processing,
compatibility testing, storage and distribution of blood and blood
components shall be stored in a safe, sanitary and orderly manner.
(a) All surfaces coming in contact with blood and blood components
intended for transfusion shall be sterile, pyrogen-free, and shall not
interact with the product in such a manner as to have an adverse effect
upon the safety, purity, potency or effectiveness of the product. All
final containers and closures for blood and blood components not
intended for transfusion shall be clean and free of surface solids and
other contaminants.
(b) Each blood collecting container and its satellite container(s),
if any, shall be examined visually for damage or evidence of
contamination prior to its use and immediately after filling. Such
examination shall include inspection for breakage of seals, when
indicated, and abnormal discoloration. Where any defect is observed, the
container shall not be used, or, if detected after filling, shall be
properly discarded.
(c) Representative samples of each lot of the following reagents or
solutions shall be tested on a regularly scheduled basis by methods
described in the Standard Operating Procedures Manual to determine their
capacity to perform as required:
------------------------------------------------------------------------
Reagent or solution Frequency of testing
------------------------------------------------------------------------
Anti-human globulin...................... Each day of use.
Blood grouping reagents.................. Do.
Lectins.................................. Do.
Antibody screening and reverse grouping Do.
cells.
Hepatitis test reagents.................. Each run.
Syphilis serology reagents............... Do.
Enzymes.................................. Each day of use.
------------------------------------------------------------------------
(d) Supplies and reagents that do not bear an expiration date shall
be stored in such a manner that the oldest is used first.
(e) Supplies and reagents shall be used in a manner consistent with
instructions provided by the manufacturer.
[[Page 52]]
(f) Items that are required to be sterile and come into contact with
blood should be disposable whenever possible.
[40 FR 53532, Nov. 18, 1975, as amended at 59 FR 23636, May 6, 1994]
Subpart E [Reserved]
Subpart F_Production and Process Controls
Sec. 606.100 Standard operating procedures.
(a) In all instances, except clinical investigations, standard
operating procedures shall comply with published additional standards in
part 640 of this chapter for the products being processed; except that,
references in part 640 relating to licenses, licensed establishments and
submission of material or data to or approval by the Director, Center
for Biologics Evaluation and Research, are not applicable to
establishments not subject to licensure under section 351 of the Public
Health Service Act.
(b) Written standard operating procedures shall be maintained and
shall include all steps to be followed in the collection, processing,
compatibility testing, storage, and distribution of blood and blood
components for transfusion and further manufacturing purposes. Such
procedures shall be available to the personnel for use in the areas
where the procedures are performed. The written standard operating
procedures shall include, but are not limited to, descriptions of the
following, when applicable:
(1) Criteria used to determine donor suitability, including
acceptable medical history criteria.
(2) Methods of performing donor qualifying tests and measurements,
including minimum and maximum values for a test or procedure when a
factor in determining acceptability.
(3) Solutions and methods used to prepare the site of phlebotomy to
give maximum assurance of a sterile container of blood.
(4) Method of accurately relating the product(s) to the donor.
(5) Blood collection procedure, including in-process precautions
taken to measure accurately the quantity of blood removed from the
donor.
(6) Methods of component preparation, including any time
restrictions for specific steps in processing.
(7) All tests and repeat tests performed on blood and blood
components during manufacturing.
(8) Pretransfusion testing, where applicable, including precautions
to be taken to identify accurately the recipient blood samples and
crossmatched donor units.
(9) Procedures for investigating adverse donor and recipient
reactions.
(10) Storage temperatures and methods of controlling storage
temperatures for all blood products and reagents as prescribed in
Sec. Sec. 600.15 and 610.53 of this chapter.
(11) Length of expiration dates, if any, assigned for all final
products as prescribed in Sec. 610.53 of this chapter.
(12) Criteria for determining whether returned blood is suitable for
reissue.
(13) Procedures used for relating a unit of blood or blood component
from the donor to its final disposition.
(14) Quality control procedures for supplies and reagents employed
in blood collection, processing and pretransfusion testing.
(15) Schedules and procedures for equipment maintenance and
calibration.
(16) Labeling procedures, including safeguards to avoid labeling
mixups.
(17) Procedures of plasmapheresis, plateletpheresis, and
leukapheresis, if performed, including precautions to be taken to ensure
reinfusion of a donor's own cells.
(18) Procedures for preparing recovered plasma, if performed,
including details of separation, pooling, labeling, storage, and
distribution.
(19) Procedures under Sec. Sec. 610.46, 610.47, and 610.48 of this
chapter:
(i) To identify previously donated blood and blood components from a
donor who later tests reactive for evidence of human immunodeficiency
virus (HIV) infection or hepatitis C virus (HCV) infection when tested
under Sec. 610.40 of this chapter, or when a blood establishment is
made aware of other reliable test results or information indicating
evidence of HIV or HCV infection;
[[Page 53]]
(ii) To quarantine in-date blood and blood components previously
donated by such a donor that are intended for use in another person or
further manufacture into injectable products, except pooled components
intended solely for further manufacturing into products that are
manufactured using validated viral clearance procedures;
(iii) To notify consignees to quarantine in-date blood and blood
components previously donated by such a donor intended for use in
another person or for further manufacture into injectable products,
except pooled components intended solely for further manufacturing into
products that are manufactured using validated viral clearance
procedures;
(iv) To determine the suitability for release, destruction, or
relabeling of quarantined in-date blood and blood components;
(v) To notify consignees of the results of the HIV or HCV testing
performed on the donors of such blood and blood components;
(vi) To notify the transfusion recipient, the recipient's physician
of record, or the recipient's legal representative that the recipient
received blood or blood components at increased risk of transmitting HIV
or HCV, respectively.
(20) Procedures for donor deferral as prescribed in Sec. 610.41 of
this chapter; and procedures for donor notification and autologous donor
referring physician notification, including procedures for the
appropriate followup if the initial attempt at notification fails, as
prescribed in Sec. 630.6 of this chapter.
(c) All records pertinent to the lot or unit maintained pursuant to
these regulations shall be reviewed before the release or distribution
of a lot or unit of final product. The review or portions of the review
may be performed at appropriate periods during or after blood
collecting, processing, compatibility testing and storing. A thorough
investigation, including the conclusions and followup, of any
unexplained discrepancy or the failure of a lot or unit to meet any of
its specifications shall be made and recorded.
(d) In addition to the requirements of this subpart and in
conformity with this section, any facility may utilize current standard
operating procedures such as the manuals of the organizations, as long
as such specific procedures are consistent with, and at least as
stringent as, the requirements contained in this part.
(1) American Association of Blood Banks.
(2) American National Red Cross.
(3) Other organizations or individual blood banks, subject to
approval by the Director, Center for Biologics Evaluation and Research.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990; 61 FR 47422, Sept. 9, 1996; 64 FR 45370, Aug.
19, 1999; 66 FR 31176, June 11, 2001; 72 FR 48798, Aug. 24, 2007]
Sec. 606.110 Plateletpheresis, leukapheresis, and plasmapheresis.
(a) The use of plateletpheresis and leukapheresis procedures to
obtain a product for a specific recipient may be at variance with the
additional standards for specific products prescribed in this part
provided that: (1) A physician has determined that the recipient must be
transfused with the leukocytes or platelets from a specific donor, and
(2) the procedure is performed under the supervision of a qualified
licensed physician who is aware of the health status of the donor, and
the physician has certified in writing that the donor's health permits
plateletpheresis or leukapheresis.
(b) Plasmapheresis of donors who do not meet the donor requirements
of Sec. Sec. 640.63, 640.64 and 640.65 of this chapter for the
collection of plasma containing rare antibodies shall be permitted only
with the prior approval of the Director, Center for Biologics Evaluation
and Research.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Subpart G_Finished Product Control
Sec. 606.120 Labeling, general requirements.
(a) Labeling operations shall be separated physically or spatially
from other operations in a manner adequate to prevent mixups.
(b) The labeling operation shall include the following labeling
controls:
[[Page 54]]
(1) Labels shall be held upon receipt, pending review and proofing
against an approved final copy, to ensure accuracy regarding identity,
content, and conformity with the approved copy.
(2) Each type of label representing different products shall be
stored and maintained in a manner to prevent mixups, and stocks of
obsolete labels shall be destroyed.
(3) All necessary checks in labeling procedures shall be utilized to
prevent errors in translating test results to container labels.
(c) All labeling shall be clear and legible.
[50 FR 35469, Aug. 30, 1985]
Sec. 606.121 Container label.
(a) The container label requirements are designed to facilitate the
use of a uniform container label for blood and blood components (except
Source Plasma) by all blood establishments.
(b) The label provided by the collecting facility and the initial
processing facility shall not be removed, altered, or obscured, except
that the label may be altered to indicate the proper name and other
information required to identify accurately the contents of a container
after blood components have been prepared.
(c) The container label shall include the following information, as
well as other specialized information as required in this section for
specific products:
(1) The proper name of the product in a prominent position, and
modifier(s), if appropriate.
(2) The name, address, registration number, and, if a licensed
product, the license number of each manufacturer.
(3) The donor, pool, or lot number relating the unit to the donor.
(4) The expiration date, including the day, month, and year, and, if
the dating period for the product is 72 hours or less, the hour of
expiration.
(5) If the product is intended for transfusion, the appropriate
donor classification statement, i.e., ``paid donor'' or ``volunteer
donor'', in no less prominence than the proper name of the product.
(i) A paid donor is a person who receives monetary payment for a
blood donation.
(ii) A volunteer donor is a person who does not receive monetary
payment for a blood donation.
(iii) Benefits, such as time off from work, membership in blood
assurance programs, and cancellation of nonreplacement fees that are not
readily convertible to cash, do not constitute monetary payment within
the meaning of this paragraph.
(6) For Whole Blood, Plasma, Platelets, and partial units of Red
Blood Cells, the volume of the product, accurate to within 10 percent; or optionally for Platelets, the volume
range within reasonable limits.
(7) The recommended storage temperature (in degrees Celsius).
(8) If the product is intended for transfusion, the statements:
(i) ``Rx only.''
(ii) ``See circular of information for indications,
contraindications, cautions, and methods of infusion.''
(iii) ``Properly identify intended recipient.''
(9) The statement: ``This product may transmit infectious agents.''
(10) Where applicable, the name and volume of source material.
(11) The statement: ``Caution: For Manufacturing Use Only'', when
applicable.
(12) If the product is intended for transfusion, the ABO and Rh
groups of the donor shall be designated conspicuously. For
Cryoprecipitated AHF, the Rh group may be omitted. The Rh group shall be
designated as follows:
(i) If the test using Anti-D Blood Grouping Reagent is positive, the
product shall be labeled: ``Rh positive.''
(ii) If the test using Anti-D Blood Grouping Reagent is negative but
the test for Du is positive, the product shall be labeled:
``Rh positive.''
(iii) If the test using Anti-D Blood Grouping Reagent is negative
and the test for Du is negative, the product shall be
labeled: ``Rh negative.''
(13) The container label must bear encoded information in a format
that is machine-readable and approved for use by the Director, Center
for Biologics Evaluation and Research.
[[Page 55]]
(i) Who is subject to this machine-readable requirement? All blood
establishments that manufacture, process, repack, or relabel blood or
blood components intended for transfusion and regulated under the
Federal Food, Drug, and Cosmetic Act or the Public Health Service Act.
(ii) What blood products are subject to this machine-readable
requirement? All blood and blood components intended for transfusion are
subject to the machine-readable information label requirement in this
section.
(iii) What information must be machine-readable? Each label must
have machine-readable information that contains, at a minimum:
(A) A unique facility identifier;
(B) Lot number relating to the donor;
(C) Product code; and
(D) ABO and Rh of the donor.
(iv) How must the machine-readable information appear The machine-
readable information must:
(A) Be unique to the blood or blood component;
(B) Be surrounded by sufficient blank space so that the machine-
readable information can be scanned correctly; and
(C) Remain intact under normal conditions of use.
(v) Where does the machine-readable information go? The machine-
readable information must appear on the label of any blood or blood
component which is or can be transfused to a patient or from which the
blood or blood component can be taken and transfused to a patient.
(d) Except for recovered plasma intended for manufacturing use or as
otherwise approved by the Director, Center for Biologics Evaluation and
Research, the paper of the container label shall be white and print
shall be solid black, with the following additional exceptions:
(1) The Rh blood group shall be printed as follows:
(i) Rh positive: Use black print on white background.
(ii) Rh negative: Use white print on black background.
(2) The proper name of the product, any appropriate modifier(s), the
donor classification statement, and the statement ``properly identify
intended recipient'' shall be printed in solid red or in solid black.
(3) The following color scheme may be used optionally for
differentiating ABO Blood groups:
------------------------------------------------------------------------
Blood group Color of label paper
------------------------------------------------------------------------
O Blue
A Yellow
B Pink
AB White
------------------------------------------------------------------------
(4) Ink colors used for the optional color coding system described
in paragraph (d)(3) of this section shall be a visual match to specific
color samples designated by the Director, Center for Biologics
Evaluation and Research.
(5) Special labels, such as those described in paragraphs (h) and
(i) of this section, may be color coded using the colors recommended in
the guideline (see paragraph (a) of this section), or colors otherwise
approved for use by the Director, Center for Biologics Evaluation and
Research.
(e) Container label requirements for particular products or groups
of products.
(1) Whole Blood labels shall include:
(i) The volume of anticoagulant.
(ii) The name of the applicable anticoagulant immediately preceding
and of no less prominence than the proper name approved for use by the
Director, Center for Biologics Evaluation and Research.
(iii) If tests for unexpected antibodies are positive, blood
intended for transfusion shall be labeled: ``Contains (name of
antibody).''
(2) Except for frozen, deglycerolized, or washed Red Blood Cell
products, red blood cell labels shall include:
(i) The volume and kind of Whole Blood, including the type of
anticoagulant, from which the product was prepared.
(ii) If tests for unexpected antibodies are positive and the product
is intended for transfusion, the statement: ``Contains (name of
antibody).''
(3) Labels for products with a dating period of 72 hours or less,
including any product prepared in a system that may compromise
sterility, shall bear the hour of expiration.
(4) If tests for unexpected antibodies are positive, Plasma intended
for
[[Page 56]]
transfusion shall be labeled: ``Contains (name of antibody).''
(5) Recovered plasma labels shall include:
(i) In lieu of an expiration date, the date of collection of the
oldest material in the container.
(ii) The statement as applicable: ``Caution: For Manufacturing Use
Only''; or ``Caution: For Use in Manufacturing Noninjectable Products
Only.'' If the recovered plasma has a reactive screening test for
evidence of infection due to a communicable disease agent(s) under Sec.
610.40 of this chapter, or is collected from a donor with a previous
record of a reactive screening test for evidence of infection due to a
communicable disease agent(s) under Sec. 610.40 of this chapter, the
recovered plasma must be labeled as required under Sec.
610.40(h)(2)(ii)(E) of this chapter.
(iii) For recovered plasma not meeting the requirements for
manufacture into licensable products, the statement: ``Not for Use in
Products Subject to License Under Section 351 of the Public Health
Service Act.''
(f) Blood and blood components determined to be unsuitable for
transfusion shall be prominently labeled: ``NOT FOR TRANSFUSION'', and
the label shall state the reason the unit is considered unsuitable. The
provision does not apply to recovered plasma labeled according to
paragraph (e)(5) of this section.
(g) [Reserved]
(h) The following additional information shall appear on the label
for blood or blood components shipped in an emergency, prior to
completion of required tests, in accordance with Sec. 640.2(f) of this
chapter:
(1) The statement: ``FOR EMERGENCY USE ONLY BY --------.''
(2) Results of any tests prescribed under Sec. Sec. 610.40, and
640.5 (a), (b), or (c) of this chapter completed before shipment.
(3) Indication of any tests prescribed under Sec. Sec. 610.40, and
640.5 (a), (b), or (c) of this chapter and not completed before
shipment.
(i) The following additional information shall appear on the label
for Whole Blood or Red Blood Cells intended for autologous infusion:
(1) Information adequately identifying the patient, e.g., name,
blood group, hospital, and identification number.
(2) Date of donation.
(3) The statement: ``FOR AUTOLOGOUS USE ONLY.''
(4) In place of the blood group label, each container of blood
intended for autologous use and obtained from a donor who fails to meet
any of the donor suitability requirements under Sec. 640.3 of this
chapter or who is reactive in the hepatitis tests prescribed under Sec.
610.40 of this chapter shall be prominently and permanently labeled:
``FOR AUTOLOGOUS USE ONLY.''
(5) Units of blood originally intended for autologous use, except
those labeled as prescribed under paragraph (i)(4) of this section, may
be issued for homologous transfusion provided the container label
complies with all applicable provisions of paragraphs (b) through (e) of
this section. In such case, the special label required under paragraph
(i) (1), (2), and (3) of this section shall be removed or otherwise
obscured.
(j) A tie-tag attached to the container may be used for providing
the information required by paragraph (e) (1)(iii), (2)(ii), and (4),
(h), or (i)(1), (2), and (3) of this section.
[50 FR 35469, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988; 55
FR 11014, Mar. 26, 1990; 57 FR 10814, Mar. 31, 1992; 59 FR 23636, May 6,
1994; 63 FR 16685, Apr. 6, 1998; 64 FR 45371, Aug. 19, 1999; 66 FR
31162, June 11, 2001; 67 FR 4907, Feb. 1, 2002; 69 FR 9171, Feb. 26,
2004; 70 FR 14984, Mar. 24, 2005]
Sec. 606.122 Instruction circular.
An instruction circular shall be available for distribution if the
product is intended for transfusion. The instruction circular shall
provide adequate directions for use, including the following
information:
(a) Instructions to mix the product before use.
(b) Instructions to use a filter in the administration equipment.
(c) The statement ``Do Not Add Medications'' or an explanation
concerning allowable additives.
(d) A description of the product, its source, and preparation,
including the
[[Page 57]]
name and proportion of the anticoagulant used in collecting the Whole
Blood from each product is prepared.
(e) Statements that the product was prepared from blood that was
negative when tested for antibody to Human Immunodeficiency Virus (HIV)
and nonreactive for hepatitis B surface antigen by FDA required tests
and nonreactive when tested for syphilis by a serologic test for
syphilis (STS).
(f) The statements: ``Warning. The risk of transmitting infectious
agents is present. Careful donor selection and available laboratory
tests do not eliminate the hazard.''
(g) The names of cryoprotective agents and other additives that may
still be present in the product.
(h) The names and results of all tests performed when necessary for
safe and effective use.
(i) The use of the product, indications, contradications, side
effects and hazards, dosage and administration recommendations.
(j) [Reserved]
(k) For Red Blood Cells, the instruction circular shall contain:
(1) Instructions to administer a suitable plasma volume expander if
Red Blood Cells are substituted when Whole Blood is the indicated
product.
(2) A warning not to add Lactated Ringer's Injection U.S.P. solution
to Red Blood Cell products.
(l) For Platelets, the instruction circular shall contain:
(1) The approximate volume of plasma from which a sample unit of
Platelets is prepared.
(2) Instructions to begin administration as soon as possible, but
not more than 4 hours after entering the container.
(m) For Plasma, the instruction circular shall contain:
(1) A warning against further processing of the frozen product if
there is evidence of breakage or thawing.
(2) Instructions to thaw the frozen product at a temperature between
30 and 37 [deg]C.
(3) When applicable, instructions to begin administration of the
product within 6 hours after thawing.
(4) Instructions to administer to ABO-group-compatible recipients.
(5) A statement that this product has the same hepatitis risk as
Whole Blood; other plasma volume expanders without this risk are
available for treating hypovolemia.
(n) For Cryoprecipitated AHF, the instruction circular shall
contain:
(1) A statement that the average potency is 80 or more International
Units of antihemophilic factor.
(2) The statement: ``Usually contains at least 150 milligrams of
fibrinogen''; or, alternatively, the average fibrinogen level determined
by assay of representative units.
(3) A warning against further processing of the product if there is
evidence of breakage or thawing.
(4) Instructions to thaw the product for no more than 15 minutes at
a temperature of between 30 and 37 [deg]C.
(5) Instructions to store at room temperature after thawing and to
begin administration as soon as possible but no more than 4 hours after
entering the container or after pooling and within 6 hours after
thawing.
(6) A statement that 0.9 percent Sodium Chloride Injection U.S.P. is
the preferred diluent.
(7) Adequate instructions for pooling to ensure complete removal of
all concentrated material from each container.
(8) The statement: ``Good patient management requires monitoring
treatment responses to Cryoprecipitated AHF transfusions with periodic
plasma factor VIII or fibrinogen assays in hemophilia A and
hypofibrinogenemic recipients, respectively.''
[50 FR 35470, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988; 64
FR 45371, Aug. 19, 1999]
Subpart H_Laboratory Controls
Sec. 606.140 Laboratory controls.
Laboratory control procedures shall include:
(a) The establishment of scientifically sound and appropriate
specifications, standards and test procedures to assure that blood and
blood components are safe, pure, potent and effective.
[[Page 58]]
(b) Adequate provisions for monitoring the reliability, accuracy,
precision and performance of laboratory test procedures and instruments.
(c) Adequate identification and handling of all test samples so that
they are accurately related to the specific unit of product being
tested, or to its donor, or to the specific recipient, where applicable.
Sec. 606.151 Compatibility testing.
Standard operating procedures for compatibility testing shall
include the following:
(a) A method of collecting and identifying the blood samples of
recipients to ensure positive identification.
(b) The use of fresh recipient serum or plasma samples less than 3
days old for all pretransfusion testing if the recipient has been
pregnant or transfused within the previous 3 months.
(c) Procedures to demonstrate incompatibility between the donor's
cell type and the recipient's serum or plasma type.
(d) A provision that, if the unit of donor's blood has not been
screened by a method that will demonstrate agglutinating, coating and
hemolytic antibodies, the recipient's cells shall be tested with the
donor's serum (minor crossmatch) by a method that will so demonstrate.
(e) Procedures to expedite transfusion in life-threatening
emergencies. Records of all such incidents shall be maintained,
including complete documentation justifying the emergency action, which
shall be signed by a physician.
[40 FR 53532, Nov. 18, 1975, as amended at 64 FR 45371, Aug. 19, 1999;
66 FR 1835, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001]
Subpart I_Records and Reports
Sec. 606.160 Records.
(a)(1) Records shall be maintained concurrently with the performance
of each significant step in the collection, processing, compatibility
testing, storage and distribution of each unit of blood and blood
components so that all steps can be clearly traced. All records shall be
legible and indelible, and shall identify the person performing the
work, include dates of the various entries, show test results as well as
the interpretation of the results, show the expiration date assigned to
specific products, and be as detailed as necessary to provide a complete
history of the work performed.
(2) Appropriate records shall be available from which to determine
lot numbers of supplies and reagents used for specific lots or units of
the final product.
(b) Records shall be maintained that include, but are not limited
to, the following when applicable:
(1) Donor records:
(i) Donor selection, including medical interview and examination and
where applicable, informed consent.
(ii) Permanent and temporary deferrals for health reasons including
reason(s) for deferral.
(iii) Donor adverse reaction complaints and reports, including
results of all investigations and followup.
(iv) Therapeutic bleedings, including signed requests from attending
physicians, the donor's disease and disposition of units.
(v) Immunization, including informed consent, identification of the
antigen, dosage and route of administration.
(vi) Blood collection, including identification of the phlebotomist.
(vii) Records to relate the donor with the unit number of each
previous donation from that donor.
(viii) Records concerning the following activities performed under
Sec. Sec. 610.46, 610.47, and 610.48 of this chapter: Quarantine;
consignee notification; testing; notification of a transfusion
recipient, the recipient's physician of record, or the recipient's legal
representative; and disposition.
(ix) Records of notification of donors deferred or determined not to
be suitable for donation, including appropriate followup if the initial
attempt at notification fails, performed under Sec. 630.6 of this
chapter.
(x) The donor's address provided at the time of donation where the
donor may be contacted within 8 weeks after donation.
(xi) Records of notification of the referring physician of a
deferred
[[Page 59]]
autologous donor, including appropriate followup if the initial
notification attempt fails, performed under Sec. 630.6 of this chapter.
(2) Processing records:
(i) Blood processing, including results and interpretation of all
tests and retests.
(ii) Component preparation, including all relevant dates and times.
(iii) Separation and pooling of recovered plasma.
(iv) Centrifugation and pooling of source plasma.
(v) Labeling, including initials of the person(s) performing the
procedure.
(3) Storage and distribution records:
(i) Distribution and disposition, as appropriate, of blood and blood
products.
(ii) Visual inspection of whole blood and red blood cells during
storage and immediately before distribution.
(iii) Storage temperature, including initialed temperature recorder
charts.
(iv) Reissue, including records of proper temperature maintenance.
(v) Emergency release of blood, including signature of requesting
physician obtained before or after release.
(4) Compatibility test records:
(i) Results of all compatibility tests, including crossmatching,
testing of patient samples, antibody screening and identification.
(ii) Results of confirmatory testing.
(5) Quality control records:
(i) Calibration and standardization of equipment.
(ii) Performance checks of equipment and reagents.
(iii) Periodic check on sterile technique.
(iv) Periodic tests of capacity of shipping containers to maintain
proper temperature in transit.
(v) Proficiency test results.
(6) Transfusion reaction reports and complaints, including records
of investigations and followup.
(7) General records:
(i) Sterilization of supplies and reagents prepared within the
facility, including date, time interval, temperature and mode.
(ii) Responsible personnel.
(iii) Biological product deviations.
(iv) Maintenance records for equipment and general physical plant.
(v) Supplies and reagents, including name of manufacturer or
supplier, lot numbers, expiration date and date of receipt.
(vi) Disposition of rejected supplies and reagents used in the
collection, processing and compatibility testing of blood and blood
components.
(c) A donor number shall be assigned to each accepted donor, which
relates the unit of blood collected to that donor, to his medical
record, to any component or blood product from that donor's unit of
blood, and to all records describing the history and ultimate
disposition of these products.
(d) Records shall be retained for such interval beyond the
expiration date for the blood or blood component as necessary to
facilitate the reporting of any unfavorable clinical reactions. You must
retain individual product records no less than 10 years after the
records of processing are completed or 6 months after the latest
expiration date for the individual product, whichever is the later date.
When there is no expiration date, records shall be retained
indefinitely.
(e) A record shall be available from which unsuitable donors may be
identified so that products from such individuals will not be
distributed.
[40 FR 53532, Nov. 18, 1975, as amended at 61 FR 47422, Sept. 9, 1996;
64 FR 45371, Aug. 19, 1999; 65 FR 66635, Nov. 7, 2000; 66 FR 31176, June
11, 2001; 72 FR 48798, Aug. 24, 2007]
Sec. 606.165 Distribution and receipt; procedures and records.
(a) Distribution and receipt procedures shall include a system by
which the distribution or receipt of each unit can be readily determined
to facilitate its recall, if necessary.
(b) Distribution records shall contain information to readily
facilitate the identification of the name and address of the consignee,
the date and quantity delivered, the lot number of the unit(s), the date
of expiration or the date of collection, whichever is applicable, or for
crossmatched blood and blood components, the name of the recipient.
(c) Receipt records shall contain the name and address of the
collecting facility, date received, donor or lot number assigned by the
collecting facility
[[Page 60]]
and the date of expiration or the date of collection, whichever is
applicable.
Sec. 606.170 Adverse reaction file.
(a) Records shall be maintained of any reports of complaints of
adverse reactions regarding each unit of blood or blood product arising
as a result of blood collection or transfusion. A thorough investigation
of each reported adverse reaction shall be made. A written report of the
investigation of adverse reactions, including conclusions and followup,
shall be prepared and maintained as part of the record for that lot or
unit of final product by the collecting or transfusing facility. When it
is determined that the product was at fault in causing a transfusion
reaction, copies of all such written reports shall be forwarded to and
maintained by the manufacturer or collecting facility.
(b) When a complication of blood collection or transfusion is
confirmed to be fatal, the Director, Office of Compliance and Biologics
Quality, Center for Biologics Evaluation and Research, shall be notified
by telephone, facsimile, express mail, or electronically transmitted
mail as soon as possible; a written report of the investigation shall be
submitted to the Director, Office of Compliance and Biologics Quality,
Center for Biologics Evaluation and Research, within 7 days after the
fatality by the collecting facility in the event of a donor reaction, or
by the facility that performed the compatibility tests in the event of a
transfusion reaction.
[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 50
FR 35471, Aug. 30, 1985; 55 FR 11014, Mar. 26, 1990; 64 FR 45371, Aug.
19, 1999; 67 FR 9586, Mar. 4, 2002]
Sec. 606.171 Reporting of product deviations by licensed manufacturers,
unlicensed registered blood establishments, and transfusion services.
(a) Who must report under this section? You, a licensed manufacturer
of blood and blood components, including Source Plasma; an unlicensed
registered blood establishment; or a transfusion service who had control
over the product when the deviation occurred, must report under this
section. If you arrange for another person to perform a manufacturing,
holding, or distribution step, while the product is in your control,
that step is performed under your control. You must establish, maintain,
and follow a procedure for receiving information from that person on all
deviations, complaints, and adverse events concerning the affected
product.
(b) What do I report under this section? You must report any event,
and information relevant to the event, associated with the
manufacturing, to include testing, processing, packing, labeling, or
storage, or with the holding or distribution, of both licensed and
unlicensed blood or blood components, including Source Plasma, if that
event meets all the following criteria:
(1) Either:
(i) Represents a deviation from current good manufacturing practice,
applicable regulations, applicable standards, or established
specifications that may affect the safety, purity, or potency of that
product; or
(ii) Represents an unexpected or unforeseeable event that may affect
the safety, purity, or potency of that product; and
(2) Occurs in your facility or another facility under contract with
you; and
(3) Involves distributed blood or blood components.
(c) When do I report under this section? You should report a
biological product deviation as soon as possible but you must report at
a date not to exceed 45-calendar days from the date you, your agent, or
another person who performs a manufacturing, holding, or distribution
step under your control, acquire information reasonably suggesting that
a reportable event has occurred.
(d) How do I report under this section? You must report on Form FDA-
3486.
(e) Where do I report under this section? You must send the
completed Form FDA-3486 to the Director, Office of Compliance and
Biologics Quality (HFM-600) (see mailing addresses in Sec. 600.2 of
this chapter) by either a paper or electronic filing:
(1) If you make a paper filing, you should identify on the envelope
that a BPDR (biological product deviation report) is enclosed; or
(2) If you make an electronic filing, you may submit the completed
Form
[[Page 61]]
FDA-3486 electronically through CBER's website at www.fda.gov/cber.
(f) How does this regulation affect other FDA regulations? This part
supplements and does not supersede other provisions of the regulations
in this chapter. All biological product deviations, whether or not they
are required to be reported under this section, should be investigated
in accordance with the applicable provisions of parts 211, 606, and 820
of this chapter.
[65 FR 66635, Nov. 7, 2000, as amended at 70 FR 14984, Mar. 24, 2005]
PART 607_ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR MANUFACTURERS OF
HUMAN BLOOD AND BLOOD PRODUCTS--Table of Contents
Subpart A_General Provisions
Sec.
607.3 Definitions.
607.7 Establishment registration and product listing of blood banks and
other firms manufacturing human blood and blood products.
Subpart B_Procedures for Domestic Blood Product Establishments
607.20 Who must register and submit a blood product list.
607.21 Times for establishment registration and blood product listing.
607.22 How and where to register establishments and list blood products.
607.25 Information required for establishment registration and blood
product listing.
607.26 Amendments to establishment registration.
607.30 Updating blood product listing information.
607.31 Additional blood product listing information.
607.35 Notification of registrant; blood product establishment
registration number and NDC Labeler Code.
607.37 Inspection of establishment registrations and blood product
listings.
607.39 Misbranding by reference to establishment registration or to
registration number.
Subpart C_Procedures for Foreign Blood Product Establishments
607.40 Establishment registration and blood product listing requirements
for foreign blood product establishments.
Subpart D_Exemptions
607.65 Exemptions for blood product establishments.
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374, 381,
393; 42 U.S.C. 262, 264, 271.
Source: 40 FR 52788, Nov. 12, 1975, unless otherwise noted.
Subpart A_General Provisions
Sec. 607.3 Definitions.
(a) The term act means the Federal Food, Drug, and Cosmetic Act
approved June 25, 1938 (52 Stat. 1040 et seq., as amended, 21 U.S.C.
301-392).
(b) Blood and blood product means a drug which consists of human
whole blood, plasma, or serum or any product derived from human whole
blood, plasma, or serum, hereinafter referred to as ``blood product.''
For the purposes of this part only, blood and blood product also means
those products that meet the definition of a device under the Federal
Food, Drug, and Cosmetic Act and that are licensed under section 351 of
the Public Health Service Act.
(c) Establishment means a place of business under one management at
one general physical location. The term includes, among others, human
blood and plasma donor centers, blood banks, transfusion services, other
blood product manufacturers and independent laboratories that engage in
quality control and testing for registered blood product establishments.
(d) Manufacture means the collection, preparation, processing or
compatibility testing by chemical, physical, biological, or other
procedures of any blood product which meets the definition of a drug as
defined in section 201(g) of the act, and including manipulation,
sampling, testing, or control procedures applied to the final product or
to any part of the process. The term includes packaging, labeling,
repackaging or otherwise changing the container, wrapper, or labeling of
any blood product package in furtherance of the distribution of the
blood product from the original place of manufacture to the person who
makes final delivery or sale to the ultimate consumer.
(e) Commercial distribution means any distribution of a blood
product except
[[Page 62]]
under the investigational use provisions of part 312 of this chapter,
but does not include internal or interplant transfer of a bulk product
substance between registered establishments within the same parent,
subsidiary, and/or affiliate company. For foreign establishments, the
term ``commercial distribution'' shall have the same meaning except that
the term shall not include distribution of any blood or blood product
that is neither imported nor offered for import into the United States.
(f) Any material change includes but is not limited to any change in
the name of the blood product, in the quantity or identity of the active
ingredient(s) or in the quantity or identity of the inactive
ingredient(s) where quantitative listing of all ingredients is required
pursuant to Sec. 607.31(a)(2) and any significant change in the
labeling of a blood product. Changes that are not significant include
changes in arrangement or printing or changes of an editorial nature.
(g) Bulk product substance means any substance that is represented
for use in a blood product and when used in the manufacturing of a blood
product becomes an active ingredient or a finished dosage form of such
product.
(h) Advertising and labeling include the promotional material
described in Sec. 202.1(l) (1) and (2) of this chapter, respectively.
(i) The definitions and interpretations contained in sections 201
and 510 of the act shall be applicable to such terms when used in this
part 607.
(j) United States agent means a person residing or maintaining a
place of business in the United States whom a foreign establishment
designates as its agent. This definition excludes mailboxes, answering
machines or services, or other places where an individual acting as the
foreign establishment's agent is not physically present.
[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990;
66 FR 59158, Nov. 27, 2001]
Sec. 607.7 Establishment registration and product listing of blood banks and
other firms manufacturing human blood and blood products.
(a) All owners or operators of establishments that engage in the
manufacturing of blood products are required to register, pursuant to
section 510 of the Federal Food, Drug, and Cosmetic Act. Registration
and listing of blood products shall comply with this part. Registration
does not permit any blood bank or similar establishment to ship blood
products in interstate commerce.
(b) Forms for registration of an establishment are obtainable on
request from the Center for Biologics Evaluation and Research (HFM-375)
(see mailing addresses in Sec. 600.2 of this chapter), or at any of the
Food and Drug Administration district offices.
(c) The completed form should be mailed to the Center for Biologics
Evaluation and Research (HFM-375) (see mailing addresses in Sec. 600.2
of this chapter).
[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990; 66 FR 59158, Nov. 27, 2001; 70 FR 14984, Mar.
24, 2005]
Subpart B_Procedures for Domestic Blood Product Establishments
Sec. 607.20 Who must register and submit a blood product list.
(a) Owners or operators of all establishments, not exempt under
section 510(g) of the act or subpart D of this part, that engage in the
manufacture of blood products shall register and submit a list of every
blood product in commercial distribution (except that registration and
listing information may be submitted by the parent, subsidiary, and/or
affiliate company for all establishments when operations are conducted
at more than one establishment and there exists joint ownership and
control among all the establishments). Blood products manufactured,
prepared, propagated, compounded, or processed in any State as defined
in section 201(a)(1) of the act must be listed whether or not the output
of such blood product establishment or any particular blood product so
listed enters interstate commerce.
[[Page 63]]
(b) Preparatory to engaging in the manufacture of blood products,
owners or operators of establishments who are submitting a biologics
license application to manufacture blood products are required to
register before the biologics license application is approved.
(c) No registration fee is required. Establishment registration and
blood product listing do not constitute an admission or agreement or
determination that a blood product is a ``drug'' within the meaning of
section 201(g) of the act.
[40 FR 52788, Nov. 12, 1975, as amended at 64 FR 56452, Oct. 20, 1999;
66 FR 59158, Nov. 27, 2001]
Sec. 607.21 Times for establishment registration and blood product listing.
The owner or operator of an establishment entering into an operation
defined in Sec. 607.3(d) shall register such establishment within 5
days after the beginning of such operation and submit a list of every
blood product in commercial distribution at the time. If the owner or
operator of the establishment has not previously entered into such
operation (defined in Sec. 607.3(d) of this chapter) for which a
license is required, registration shall follow within 5 days after the
submission of a biologics license application in order to manufacture
blood products. Owners or operators of all establishments so engaged
shall register annually between November 15 and December 31 and shall
update their blood product listing information every June and December.
[40 FR 52788, Nov. 12, 1975, as amended at 64 FR 56453, Oct. 20, 1999]
Sec. 607.22 How and where to register establishments and list blood
products.
(a) The first registration of an establishment shall be on Form FD-
2830 (Blood Establishment Registration and Product Listing) obtainable
on request from the Department of Health and Human Services, Food and
Drug Administration, Center for Biologics Evaluation and Research (HFM-
375), (see mailing addresses in Sec. 600.2 of this chapter), or from
Food and Drug Administration district offices. Subsequent annual
registration shall also be accomplished on Form FD-2830, which will be
furnished by the Food and Drug Administration before November 15 of each
year to establishments whose product registration for that year was
validated under Sec. 607.35. The completed form shall be mailed to the
preceding address before December 31 of that year.
(b) The first list of blood products and subsequent June and
December updatings shall be on Form FD-2830, obtainable upon request as
described in paragraph (a) of this section.
[66 FR 59158, Nov. 27, 2001, as amended at 70 FR 14984, Mar. 24, 2005]
Sec. 607.25 Information required for establishment registration and blood
product listing.
(a) Form FD-2830 (Blood Establishment Registration and Product
Listing) requires furnishing or confirming registration information
required by the act. This information includes the name and street
address of the establishment, including post office code; all trade
names used by the establishment; the kind of ownership or operation
(that is, individually owned partnership, or corporation); and the name
of the owner or operator of such establishment. The term ``name of the
owner or operator'' shall include in the case of a partnership the name
of each partner, and in the case of a corporation the name and title of
each corporate officer and director and the name of the State of
incorporation. The information required shall be given separately for
each establishment, as defined in Sec. 607.3(c).
(b) Form FD-2830 also requires furnishing blood product listing
information required by the act as follows:
(1) A list of blood products, including bulk product substances as
well as finished dosage forms, by established name as defined in section
502(e) of the act and by proprietary name, which are being manufactured
for commercial distribution and which have not been included in any list
previously submitted on Form FD-2830 (Blood Establishment Registration
and Product Listing) or Form FD-2250 (National Drug Code Directory
Input).
(2) For each blood product so listed which is subject to section 351
of the Public Health Service Act, the license
[[Page 64]]
number of the manufacturer issued by the Center for Biologics Evaluation
and Research, Food and Drug Administration.
(3) For each blood product listed, the registration number of the
parent establishment. An establishment not owned, operated, or
controlled by another firm or establishment is its own parent
establishment.
[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11013, Mar. 26, 1990; 66 FR 59158, Nov. 27, 2001]
Sec. 607.26 Amendments to establishment registration.
Changes in individual ownership, corporate or partnership structure,
location, or blood-product handling activity shall be submitted on Form
FDA-2830 (Blood Establishment Registration and Product Listing) as an
amendment to registration within 5 days of such changes. Changes in the
names of officers and directors of the corporations do not require such
amendment but must be shown at time of annual registration.
[40 FR 52788, Nov. 12, 1975, as amended at 66 FR 59158, Nov. 27, 2001]
Sec. 607.30 Updating blood product listing information.
(a) After submission of the initial blood product listing
information, every person who is required to list blood products
pursuant to Sec. 607.20 shall submit on Form FD-2830 (Blood
Establishment Registration and Product Listing) during each subsequent
June and December, or at the discretion of the registrant at the time
the change occurs, the following information:
(1) A list of each blood product introduced by the registrant for
commercial distribution which has not been included in any list
previously submitted. All of the information required by Sec. 607.25(b)
shall be provided for each such blood product.
(2) A list of each blood product formerly listed pursuant to Sec.
607.25(b) for which commercial distribution has been discontinued,
including for each blood product so listed the identity by established
name and proprietary name, and date of discontinuance. It is requested
but not required that the reason for discontinuance of distribution be
included with this information.
(3) A list of each blood product for which a notice of
discontinuance was submitted pursuant to paragraph (a)(2) of this
section and for which commercial distribution has been resumed,
including for each blood product so listed the identity by established
name as defined in section 502(e) of the act and by any proprietary
name, the date of resumption, and any other information required by
Sec. 607.25(b) not previously submitted.
(4) Any material change in any information previously submitted.
(b) When no changes have occurred since the previously submitted
list, no listing information is required.
Sec. 607.31 Additional blood product listing information.
(a) In addition to the information routinely required by Sec. Sec.
607.25 and 607.30, the Director of the Center for Biologics Evaluation
and Research may require submission of the following information by
letter or by Federal Register notice:
(1) For a particular blood product so listed, upon request made by
the Director of the Center for Biologics Evaluation and Research for
good cause, a copy of all advertisements.
(2) For a particular blood product so listed, upon a finding by the
Director of the Center for Biologics Evaluation and Research that it is
necessary to carry out the purposes of the act, a quantitative listing
of all ingredients.
(3) For each registrant, upon a finding by the Director of the
Center for Biologics Evaluation and Research that it is necessary to
carry out the purposes of the act, a list of each listed blood product
containing a particular ingredient.
(b) [Reserved]
[66 FR 59158, Nov. 27, 2001]
Sec. 607.35 Notification of registrant; blood product establishment
registration number and NDC Labeler Code.
(a) The Director of the Center for Biologics Evaluation and Research
will provide to the registrant a validated
[[Page 65]]
copy of Form FD-2830 (Blood Establishment Registration and Product
Listing) as evidence of registration. This validated copy will be sent
to the location shown for the registering establishment, and a copy will
be sent to the reporting official if at another address. A permanent
registration number will be assigned to each blood product establishment
registered in accordance with these regulations.
(b) If a registered blood product establishment has not previously
participated in the National Drug Code system, or in the National Health
Related Items Code system, the National Drug Code (NDC) numbering system
shall be used in assigning the first five numeric characters, otherwise
known as the Labeler Code, of the 10-character NDC Code. The Labeler
Code identifies the manufacturer.
(c) Although establishment registration and blood product listing
are required as described in Sec. 607.20, validation of registration
and the assignment of a NDC Labeler Code do not, in themselves,
establish that the holder of the registration is legally qualified to
deal in such products.
[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 66
FR 59159, Nov. 27, 2001]
Sec. 607.37 Inspection of establishment registrations and blood product
listings.
(a) A copy of the Form FD-2830 (Blood Establishment Registration and
Product Listing) filed by the registrant will be available for
inspection under section 510(f) of the act, at the Department of Health
and Human Services, Food and Drug Administration, Office of
Communication, Training and Manufacturers' Assistance (HFM-40), Center
for Biologics Evaluation and Research (see mailing addresses in Sec.
600.2 of this chapter). In addition, for domestic firms, the same
information will be available for inspection at each of the Food and
Drug Administration district offices for firms within the geographical
area of such district office. Upon request and receipt of a self-
addressed stamped envelope, verification of registration number, or
location of registered establishment will be provided. The following
information submitted under the blood product listing requirements is
illustrative of the type of information that will be available for
public disclosure when it is compiled:
(1) A list of all blood products.
(2) A list of all blood products manufactured by each establishment.
(3) A list of blood products discontinued.
(4) All data or information that has already become a matter of
public knowledge.
(b) Requests for information regarding blood establishment
registrations and blood product listings should be directed to the
Department of Health and Human Services, Food and Drug Administration,
Office of Communication, Training and Manufacturers' Assistance (HFM-
40), Center for Biologics Evaluation and Research (see mailing addresses
in Sec. 600.2 of this chapter).
[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55
FR 11014, Mar. 26, 1990; 66 FR 59159, Nov. 27, 2001; 70 FR 14984, Mar.
24, 2005]
Sec. 607.39 Misbranding by reference to establishment registration or to
registration number.
Registration of an establishment or assignment of a registration
number or assignment of a NDC number does not in any way denote approval
of the firm or its products. Any representation that creates an
impression of official approval because of establishment registration or
possession of registration number or NDC number is misleading and
constitutes misbranding.
Subpart C_Procedures for Foreign Blood Product Establishments
Sec. 607.40 Establishment registration and blood product listing
requirements for foreign blood product establishments.
(a) Every foreign establishment shall comply with the establishment
registration and blood product listing requirements contained in subpart
B of this part, unless exempt under subpart D of this part or unless the
blood product enters a foreign trade zone and is re-exported from that
foreign trade zone without having entered U. S. commerce.
[[Page 66]]
(b) No blood product may be imported or offered for import into the
United States unless it is the subject of a blood product listing as
required under subpart B of this part and is manufactured, prepared,
propagated, compounded, or processed at a registered foreign
establishment; however, this restriction does not apply to a blood
product imported or offered for import under the investigational use
provisions of part 312 of this chapter or to a blood product imported
under section 801(d)(4) of the act. The establishment registration and
blood product listing information shall be in the English language.
(c) Each foreign establishment required to register under paragraph
(a) of this section shall, as part of the establishment registration and
blood product listing, submit the name and address of the establishment
and the name of the individual responsible for submitting establishment
registration and blood product listing information. Any changes in this
information shall be reported to the Food and Drug Administration at the
intervals specified for updating establishment registration information
in Sec. 607.26 and blood product listing information in Sec.
607.30(a).
(d) Each foreign establishment required to register under paragraph
(a) of this section shall submit the name, address, and phone number of
its United States agent as part of its initial and updated registration
information in accordance with subpart B of this part. Each foreign
establishment shall designate only one United States agent.
(1) The United States agent shall reside or maintain a place of
business in the United States.
(2) Upon request from FDA, the United States agent shall assist FDA
in communications with the foreign establishment, respond to questions
concerning the foreign establishment's products that are imported or
offered for import into the United States, and assist FDA in scheduling
inspections of the foreign establishment. If the agency is unable to
contact the foreign establishment directly or expeditiously, FDA may
provide information or documents to the United States agent, and such an
action shall be considered to be equivalent to providing the same
information or documents to the foreign establishment.
(3) The foreign establishment or the United States agent shall
report changes in the United States agent's name, address, or phone
number to FDA within 10-business days of the change.
[66 FR 59159, Nov. 27, 2001]
Subpart D_Exemptions
Sec. 607.65 Exemptions for blood product establishments.
The following classes of persons are exempt from registration and
blood product listing in accordance with this part 607 under the
provisions of section 510(g)(1), (g)(2), and (g)(3) of the act, or
because the Commissioner of Food and Drugs has found, under section
510(g)(5), that such registration is not necessary for the protection of
the public health. The exemptions in paragraphs (a), (b), (f), and (g)
of this section are limited to those classes of persons located in any
State as defined in section 201(a)(1) of the act.
(a) Pharmacies that are operating under applicable local laws
regulating dispensing of prescription drugs and that are not
manufacturing blood products for sale other than in the regular course
of the practice of the profession of pharmacy including the business of
dispensing and selling blood products at retail. The supplying by such
pharmacies of blood products to a practitioner licensed to administer
such blood products for his use in the course of his professional
practice or to other pharmacies to meet temporary inventory shortages
are not acts which require such pharmacies to register.
(b) Practitioners who are licensed by law to prescribe or administer
drugs and who manufacture blood products solely for use in the course of
their professional practice.
(c) Persons who manufacture blood products which are not for sale,
rather, are solely for use in research, teaching, or analysis, including
laboratory samples.
(d) Carriers, by reason of their receipt, carriage, holding, or
delivery of
[[Page 67]]
blood products in the usual course of business as carriers.
(e) Persons who engage solely in the manufacture of in vitro
diagnostic blood products and reagents not subject to licensing under
section 351 of the Public Health Service Act (42 U.S.C. 262). This
paragraph does not exempt such persons from registration and listing for
medical devices required under part 807 of this chapter.
(f) Transfusion services which are a part of a facility that is
certified under the Clinical Laboratory Improvement Amendments of 1988
(42 U.S.C. 263a) and 42 CFR part 493 or has met equivalent requirements
as determined by the Centers for Medicare and Medicaid Services and
which are engaged in the compatibility testing and transfusion of blood
and blood components, but which neither routinely collect nor process
blood and blood components. The collection and processing of blood and
blood components in an emergency situation as determined by a
responsible person and documented in writing, therapeutic collection of
blood or plasma, the preparation of recovered human plasma for further
manufacturing use, or preparation of red blood cells for transfusion are
not acts requiring such transfusion services to register.
[40 FR 52788, Nov. 12, 1975, as amended at 43 FR 37997, Aug. 25, 1978;
45 FR 85729, Dec. 30, 1980; 49 FR 34449, Aug. 31, 1984; 66 FR 31162,
June 11, 2001; 66 FR 59159, Nov. 27, 2001; 72 FR 45886, August 16, 2007]
PART 610_GENERAL BIOLOGICAL PRODUCTS STANDARDS--Table of Contents
Subpart A_Release Requirements
Sec.
610.1 Tests prior to release required for each lot.
610.2 Requests for samples and protocols; official release.
Subpart B_General Provisions
610.9 Equivalent methods and processes.
610.10 Potency.
610.11 General safety.
610.11a Inactivated influenza vaccine, general safety test.
610.12 Sterility.
610.13 Purity.
610.14 Identity.
610.15 Constituent materials.
610.16 Total solids in serums.
610.17 Permissible combinations.
610.18 Cultures.
Subpart C_Standard Preparations and Limits of Potency
610.20 Standard preparations.
610.21 Limits of potency.
Subpart D_Mycoplasma
610.30 Test for Mycoplasma.
Subpart E_Testing Requirements for Communicable Disease Agents
610.40 Test requirements.
610.41 Donor deferral.
610.42 Restrictions on use for further manufacture of medical devices.
610.44 Use of reference panels by manufacturers of test kits.
610.46 Human immunodeficiency virus (HIV) ``lookback'' requirements.
610.47 Hepatitis C virus (HCV) ``lookback'' requirements.
610.48 Hepatitis C virus (HCV) ``lookback'' requirements based on review
of historical testing records.
Subpart F_Dating Period Limitations
610.50 Date of manufacture.
610.53 Dating periods for licensed biological products .
Subpart G_Labeling Standards
610.60 Container label.
610.61 Package label.
610.62 Proper name; package label; legible type.
610.63 Divided manufacturing responsibility to be shown.
610.64 Name and address of distributor.
610.65 Products for export.
610.67 Bar code label requirements.
610.68 Exceptions or alternatives to labeling requirements for
biological products held by the Strategic National Stockpile.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d,
360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 264.
Source: 38 FR 32056, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
[[Page 68]]
Subpart A_Release Requirements
Sec. 610.1 Tests prior to release required for each lot.
No lot of any licensed product shall be released by the manufacturer
prior to the completion of tests for conformity with standards
applicable to such product. Each applicable test shall be made on each
lot after completion of all processes of manufacture which may affect
compliance with the standard to which the test applies. The results of
all tests performed shall be considered in determining whether or not
the test results meet the test objective, except that a test result may
be disregarded when it is established that the test is invalid due to
causes unrelated to the product.
Sec. 610.2 Requests for samples and protocols; official release.
(a) Licensed biological products regulated by CBER. Samples of any
lot of any licensed product together with the protocols showing results
of applicable tests, may at any time be required to be sent to the
Director, Center for Biologics Evaluation and Research (see mailing
addresses in Sec. 600.2 of this chapter). Upon notification by the
Director, Center for Biologics Evaluation and Research, a manufacturer
shall not distribute a lot of a product until the lot is released by the
Director, Center for Biologics Evaluation and Research: Provided, That
the Director, Center for Biologics Evaluation and Research, shall not
issue such notification except when deemed necessary for the safety,
purity, or potency of the product.
(b) Licensed biological products regulated by CDER. Samples of any
lot of any licensed product together with the protocols showing results
of applicable tests, may at any time be required to be sent to the
Director, Center for Drug Evaluation and Research (see mailing addresses
in Sec. 600.2) for official release. Upon notification by the Director,
Center for Drug Evaluation and Research, a manufacturer shall not
distribute a lot of a biological product until the lot is released by
the Director, Center for Drug Evaluation and Research: Provided, That
the Director, Center for Drug Evaluation and Research shall not issue
such notification except when deemed necessary for the safety, purity,
or potency of the product.
[40 FR 31313, July 25, 1975, as amended by 49 FR 23834, June 8, 1984; 50
FR 10941, Mar. 19, 1985; 55 FR 11013 and 11014, Mar. 26, 1990; 67 FR
9587, Mar. 4, 2002; 70 FR 14984, Mar. 24, 2005]
Subpart B_General Provisions
Sec. 610.9 Equivalent methods and processes.
Modification of any particular test method or manufacturing process
or the conditions under which it is conducted as required in this part
or in the additional standards for specific biological products in parts
620 through 680 of this chapter shall be permitted only under the
following conditions:
(a) The applicant presents evidence, in the form of a license
application, or a supplement to the application submitted in accordance
with Sec. 601.12(b) or (c), demonstrating that the modification will
provide assurances of the safety, purity, potency, and effectiveness of
the biological product equal to or greater than the assurances provided
by the method or process specified in the general standards or
additional standards for the biological product; and
(b) Approval of the modification is received in writing from the
Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research.
[62 FR 39903, July 24, 1997, as amended at 70 FR 14984, Mar. 24, 2005]
Sec. 610.10 Potency.
Tests for potency shall consist of either in vitro or in vivo tests,
or both, which have been specifically designed for each product so as to
indicate its potency in a manner adequate to satisfy the interpretation
of potency given by the definition in Sec. 600.3(s) of this chapter.
Sec. 610.11 General safety.
A general safety test for the detection of extraneous toxic
contaminants
[[Page 69]]
shall be performed on biological products intended for administration to
humans. The general safety test is required in addition to other
specific tests prescribed in the additional standards for individual
products in this subchapter, except that, the test need not be performed
on those products listed in paragraph (g) of this section. The general
safety test shall be performed as specified in this section, unless:
Modification is prescribed in the additional standards for specific
products, or variation is approved as a supplement to the product
license under Sec. 610.9.
(a) Product to be tested. The general safety test shall be conducted
upon a representative sample of the product in the final container from
every final filling of each lot of the product. If any product is
processed further after filling, such as by freeze-drying,
sterilization, or heat treatment, the test shall be conducted upon a
sample from each filling of each drying chamber run, sterilization
chamber, or heat treatment bath.
(b) Test animals. Only overtly healthy guinea pigs weighing less
than 400 grams each and mice weighing less than 22 grams each shall be
used. The animals shall not have been used previously for any test
purpose.
(c) Procedure. The duration of the general safety test shall be 7
days for both species, except that a longer period may be established
for specific products in accordance with Sec. 610.9. Once the
manufacturer has established a specific duration of the test period for
a specific product, it cannot be varied subsequently, except, in
accordance with Sec. 610.9. Each test animal shall be weighed and the
individual weights recorded immediately prior to injection and on the
last day of the test. Each animal shall be observed every working day.
Any animal response including any which is not specific for or expected
from the product and which may indicate a difference in its quality
shall be recorded on the day such response is observed. The test product
shall be administered as follows:
(1) Liquid product or freeze-dried product which has been
reconstituted as directed on the label. Inject intraperitoneally 0.5
milliliter of the liquid product or the reconstituted product into each
of at least two mice, and 5.0 milliliters of the liquid product or the
reconstituted product into each of at least two guinea pigs.
(2) Freeze-dried product for which the volume of reconstitution is
not indicated on the label. The route of administration, test dose, and
diluent shall be as approved in accordance with Sec. 610.9. Administer
the test product as approved on at least two mice and at least two
guinea pigs.
(3) Nonliquid products other than freeze-dried product. The route of
administration, test dose, and diluent shall be as in accordance with
Sec. 610.9. Dissolve or grind and suspend the product in the approved
diluent. Administer the test product as approved on at least two mice
and at least two guinea pigs.
(d) Test requirements. A safety test is satisfactory if all animals
meet all of the following requirements:
(1) They survive the test period.
(2) They do not exhibit any response which is not specific for or
expected from the product and which may indicate a difference in its
quality.
(3) They weigh no less at the end of the test period than at the
time of injection.
(e) Repeat tests--(1) First repeat test. If a filling fails to meet
the requirements of paragraph (d) of this section in the initial test, a
repeat test may be conducted on the species which failed the initial
test, as prescribed in paragraph (c) of this section. The filling is
satisfactory only if each retest animal meets the requirements
prescribed in paragraph (d) of this section.
(2) Second repeat test. If a filling fails to meet the requirements
of the first repeat test, a second repeat test may be conducted on the
species which failed the test: Provided, That 50 percent of the total
number of animals in that species has survived the initial and first
repeat tests. The second repeat test shall be conducted as prescribed in
paragraph (c) of this section, except that the number of animals shall
be twice that used in the first repeat test. The filling is satisfactory
only if each second repeat test animal meets the requirements prescribed
in paragraph (d) of this section.
[[Page 70]]
(f) [Reserved]
(g) Exceptions--(1) The test prescribed in this section need not be
performed for Whole Blood, Red Blood Cells, Cryoprecipitated AHF,
Platelets, Plasma, or Cellular Therapy Products.
(2) For products other than those identified in paragraph (g)(1) of
this section, a manufacturer may request from the Director, Center for
Biologics Evaluation and Research or the Director, Center for Drug
Evaluation and Research (see mailing addresses in Sec. 600.2 of this
chapter), an exemption from the general safety test. The manufacturer
must submit information as part of a biologics license application
submission or supplement to an approved biologics license application
establishing that because of the mode of administration, the method of
preparation, or the special nature of the product a test of general
safety is unnecessary to assure the safety, purity, and potency of the
product or cannot be performed. The request must include alternate
procedures, if any, to be performed. The Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research, upon finding that the manufacturer's request justifies an
exemption, may exempt the product from the general safety test subject
to any condition necessary to assure the safety, purity, and potency of
the product.
[41 FR 10891, Mar. 15, 1976, as amended at 49 FR 15187, Apr. 18, 1984;
49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 15607, Apr.
25, 1986; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR
19403, Apr. 20, 1998; 63 FR 41718, Aug. 5, 1998; 68 FR 10160, Mar. 4,
2003; 70 FR 14984, Mar. 24, 2005]
Sec. 610.11a Inactivated influenza vaccine, general safety test.
For inactivated influenza vaccine, the general safety test shall be
conducted in the manner indicated in Sec. 610.11 of this chapter except
that, with reference to guinea pigs, the test shall be satisfied if the
product provides satisfactory results using either the subcutaneous or
intraperitoneal injection of 5.0 milliliters of inactivated influenza
vaccine into each guinea pig. The requirements for general safety for
inactivated influenza vaccine shall not be considered to be satisfied
unless each lot of influenza vaccine is assayed for endotoxin in
comparison to a reference preparation provided by the Food and Drug
Administration, and such lot is found to contain no more endotoxin than
the reference preparation.
[39 FR 40016, Nov. 13, 1974]
Sec. 610.12 Sterility.
Except as provided in paragraphs (f) and (g) of this section, the
sterility of each lot of each product shall be demonstrated by the
performance of the tests prescribed in paragraphs (a) and (b) of this
section for both bulk and final container material.
(a) The test. Bulk material shall be tested separately from final
container material and material from each final container shall be
tested in individual test vessels as follows:
(1) Using Fluid Thioglycollate Medium--(i) Bulk and final container
material. The volume of product, as required by paragraph (d) of this
section (hereinafter referred to also as the ``inoculum''), from samples
of both bulk and final container material, shall be inoculated into test
vessels of Fluid Thioglycollate Medium. The inoculum and medium shall be
mixed thoroughly and incubated at a temperature of 30 to 35 [deg]C for a
test period of no less than 14 days and examined visually for evidence
of growth on the third, fourth, or fifth day, and on the seventh or
eighth day, and on the last day of the test period. Results of each
examination shall be recorded. If the inoculum renders the medium turbid
so that the absence of growth cannot be determined reliably by visual
examination, portions of this turbid medium in amounts of no less than
1.0 milliliter shall be transferred on the third, fourth, or fifth day
of incubation, from each of the test vessels and inoculated into
additional vessels of the medium. The material in the additional vessels
shall be incubated at a temperature of 30 to 35 [deg]C for no less than
14 days. Notwithstanding such transfer of material, examination of the
original vessels shall be continued as prescribed above. The additional
test vessels shall be examined visually for evidence of growth on the
third, fourth, or fifth day of incubation, and on the seventh or eighth
[[Page 71]]
day, and on the last day of the incubation period. If growth appears,
repeat tests may be performed as prescribed in paragraph (b) of this
section and interpreted as specified in paragraph (c) of this section.
(ii) Final container material containing a mercurial preservative.
In addition to the test prescribed in paragraph (a)(1)(i) of this
section, final container material containing a mercurial preservative
shall be tested using Fluid Thioglycollate Medium following the
procedures prescribed in such subparagraph, except that the incubation
shall be at a temperature of 20 to 25 [deg]C.
(2) Using Soybean-Casein Digest Medium. Except for products
containing a mercurial preservative, a test shall be made on final
container material, following the procedures prescribed in paragraph
(a)(1)(i) of this section, except that the medium shall be Soybean-
Casein Digest Medium and the incubation shall be at a temperature of 20
to 25 [deg]C.
(b) Repeat tests. If growth appears in any of the test media during
testing of either bulk or final container material, the test may be
repeated to rule out faulty test procedures as follows:
(1) Repeat bulk test. Only one repeat bulk test may be conducted.
The volume of inoculum to be used for the repeat bulk test shall be as
prescribed in paragraph (d)(1) of this section. The repeat test shall be
performed using the procedure prescribed in paragraph (a)(1)(i) of this
section.
(2) First repeat final container test. The number of test samples
and the volumes of product used for the first repeat test shall be as
prescribed in paragraph (d)(2) of this section. For products that do not
contain a mercurial preservative, the repeat test shall be performed,
using both Fluid Thioglycollate Medium and Soybean-Casein Digest Medium,
following the procedures prescribed in paragraphs (a)(1)(i) and (a)(2),
respectively, of this section. If the product contains a mercurial
preservative, the repeat test shall be performed using Fluid
Thioglycollate Medium and the procedures prescribed in paragraphs (a)(1)
(i) and (ii) of this section.
(3) Second repeat final container test. If growth appears in any of
the first repeat final container tests, all tests of the first repeat
final container test shall be repeated, provided there was no evidence
of growth in any test of the bulk material. The test samples used for
the second repeat final container test shall be twice the number used
for the first repeat final container test.
(c) Interpretation of test results. The results of all tests
performed on a lot shall be considered in determining whether or not the
lot meets the requirements for sterility, except that tests may be
excluded when demonstrated by adequate controls to be invalid. The lot
meets the test requirements if no growth appears in the tests prescribed
in paragraph (a) of this section. If repeat tests are performed, the lot
meets the test requirements if no growth appears in the tests prescribed
in paragraph (b)(2) or (3) of this section, whichever is applicable.
(d) Test samples and volumes--(1) Bulk. Each sample for the bulk
sterility test shall be representative of the bulk material and the
volume tested shall be no less than 10 ml. (Note exceptions in paragraph
(g) of this section.)
(2) Final containers. The sample used for each test medium or each
incubation temperature of a test medium for the final container and
first repeat final container test shall be no less than 20 final
containers from each filling of each lot, selected to represent all
stages of filling from the bulk vessel. If the amount of material in the
final container is 1.0 milliliter or less, the entire contents shall be
tested. If the amount of material in the final container is more than
1.0 milliliter, the volume tested shall be the largest single dose
recommended by the manufacturer or 1.0 milliliter, whichever is larger,
but no more than 10 milliliters of material or the entire contents from
a single final container need be tested. If more than 2 filling
machines, each with either single or multiple filling stations, are used
for filling one lot, no less than 10 filled containers shall be tested
from each filling machine for each test medium or each incubation
temperature condition, but no more than 100 containers of each lot need
be tested. The items tested shall be representative of each filling
assembly
[[Page 72]]
and shall be selected to represent all stages of the filling operation.
(Note exceptions in paragraph (g) of this section.)
(e) Culture medium--(1) Formulae. (i) The formula for Fluid
Thioglycollate Medium is as follows:
Fluid Thioglycollate Medium
1-cystine................................ 0.5 gm.
Sodium chloride.......................... 2.5 gm.
Dextrose (C6H12O6[middot]H2)O)........... 5.5 gm.
Granular agar (less than 15% moisture by 0.75 gm.
weight).
Yeast extract (water-soluble)............ 5.0 gm.
Pancreatic digest of casein.............. 15.0 gm.
Purified water........................... 1,000.0 ml.
Sodium thioglycollate (or thioglycolic 0.5 gm.
acid--0.3 ml).
Resazurin (0.10% solution, 1.0 ml.
freshly prepared).
pH after sterilization 7.10.2.
(ii) The formula for Soybean-Casein Digest Medium is as follows:
Soybean-Casein Digest Medium
Pancreatic Digest of Casein.............. 17.0 gm.
Papaic Digest of Soybean Meal............ 3.0 gm.
Sodium Chloride.......................... 5.0 gm.
Dibasic Potassium Phosphate.............. 2.5 gm.
Dextrose (C6H12O6[middot]H2O)............ 2.5 gm.
Purified water........................... 1,000.0 ml.
pH after sterilization 7.30.2.
(2) Culture media requirements--(i) Definition of a lot of culture
medium and test requirements. A lot of culture medium is that quantity
of uniform material identified as having been thoroughly mixed in a
single vessel, dispensed into a group of vessels of the same composition
and design, sterilized in a single autoclave run, and identified in a
manner to distinguish one lot from another. Each lot of culture medium
shall be tested for its growth-promoting qualities unless it meets the
exception for dehydrated culture medium described in this subpart. The
growth-promoting quality test shall be performed on the smallest sized
vessel used in an autoclave run. When using a single batch of dehydrated
culture medium, a manufacturer need not perform growth-promoting tests
on each lot of prepared liquid medium, provided that a validation
program exists for autoclaves used to sterilize the culture medium, and
the manufacturer has received approval for this practice from the
Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research.
(ii) Test organisms, strains, characteristics, identity, and
verification. Two or more strains of microorganisms that are exacting in
their nutritive and aerobic/anaerobic requirements shall be used to test
the growth-promoting qualities of each lot of test medium. When using
Fluid Thioglycollate medium, both an aerobic and an anaerobic test
microorganism shall be chosen. When using Soybean Casein Digest Medium,
the yeast, Candida albicans, shall be one of the two test microorganisms
chosen. Manufacturers shall choose the strains of microorganisms from
the chart in this paragraph.
------------------------------------------------------------------------
Incubation
Medium Test microorganisms temperature
------------------------------------------------------------------------
Spore-formers
Fluid Thioglycollate........... 1. Bacillus subtilis 30 to 35
(ATCC No. 6633). [deg]C.
2. Clostridium Do.
sporogenes (ATCC No.
11437).
Non-spore-formers
3. Candida albicans Do.
(ATCC No. 10231).
4. Micrococcus luteus Do.
(ATCC No. 9341).
5. Bacteroides Do.
vulgatus (ATCC No.
8482).
Spore-formers
Soybean-Casein Digest.......... 1. Bacillus subtilis 20 to 25
(ATCC No. 6633). [deg]C.
Non-spore-formers
2. Candida albicans Do.
(ATCC No. 10231).
3. Micrococcus luteus Do.
(ATCC No. 9341).
------------------------------------------------------------------------
ATCC strains of microorganisms described in this section are
available from the American Type Culture Collection, 10801 University
Blvd., Manassas, VA 20110. Periodic tests shall be performed to verify
the integrity of the test organisms in accordance with Sec. 610.18 (a)
and (b). The results of these
[[Page 73]]
periodic tests shall be recorded and retained in accordance with Sec.
600.12(b) of this chapter.
(iii) Storage and maintenance of cultures of test organisms.
Cultures of the test organisms used to determine the growth-promoting
qualities of the medium shall be stored in a manner that will prevent
cross contamination or loss of identity, at a temperature and by a
method that will retain the initial characteristics of the organisms and
ensure freedom from contamination and deterioration. If the test
organisms are stored in the freeze-dried state, or frozen, they shall be
reconstituted or thawed, whichever is applicable, and plated
periodically to verify the colony count of the suspension. If the test
suspensions are stored in a state other than freeze-dried or frozen,
they shall be plated, and a colony count shall be performed at the time
of each growth-promoting quality test to assure that not more than 100
organisms are used per test vessel. The results of tests for
verification of the colony count shall be recorded and retained in
accordance with Sec. 600.12(b) of this chapter.
(iv) Storage and condition of media. A medium shall not be used if
the extent of evaporation affects its fluidity, nor shall it be reused
in a sterility test of the product. Fluid Thioglycollate Medium shall be
stored in the dark at room temperature if the vessels are unsealed.
Sealed vessels shall be stored at the manufacturer's specified storage
temperature. Fluid Thioglycollate Medium shall not be used if more than
the upper one-third of the medium has acquired a pink color. The medium
may be restored once by heating on a steam bath or in free-flowing steam
until the pink color disappears. The design of the test vessel for Fluid
Thioglycollate Medium shall provide favorable aerobic and anaerobic
conditions for growth of the microorganisms throughout the test period.
Soybean-Casein Digest Medium shall be stored in the dark at 20 to 25
[deg]C. Unsealed vessels of either medium may be stored for more than 10
days at the proper temperature, provided they are tested monthly for
growth-promotion and found to be satisfactory. Sealed vessels of either
medium may be stored at the proper temperature for a period of time not
to exceed 1 year, provided they are tested for growth-promotion every 3
months and found to be satisfactory. The results of such testing shall
be recorded and retained in accordance with Sec. 600.12(b) of this
chapter.
(v) Criteria for a satisfactory growth-promoting quality test. (a)
One hundred or fewer organisms of each strain tested shall be used. The
test is satisfactory if evidence of growth appears within 7 days in all
vessels inoculated. If a lot of medium fails to support the growth of
any test organism, or if the test results show that more than 100
organisms of a strain were used or are necessary to promote growth in
the lot of medium being tested, or if the growth is not a pure culture
of the test organism, a second test may be performed. If it fails the
second test, the lot of medium shall be rejected.
(b) Inoculated Fluid Thioglycollate Medium shall be incubated at 30
to 35 [deg]C for 7 days. If the test medium is to be used in determining
the sterility of a product containing a mercurial preservative, a second
test shall be performed in accordance with paragraph (e)(2)(v)(a) of
this section, except that the test shall be incubated at 20 to 25 [deg]C
for 7 days. Inoculated Soybean-Casein Digest Medium shall be incubated
at 20 to 25 [deg]C for 7 days. The sterility of each lot of medium shall
be confirmed by the incubation of uninoculated control test vessels for
7 days at the temperature(s) for that particular medium. The lot of
medium is satisfactory if no growth is observed in the control test
vessels within the incubation period. The tests for growth-promoting
qualities of culture media may be performed simultaneously with
sterility testing of biological products, provided the sterility test is
considered invalid if the test medium shows no growth response.
(vi) Volume of culture medium. The volume of each culture medium
shall be determined for each bulk and final container sterility test
required for each product. The ratio of the volume of inoculum to the
volume of culture medium shall result in a dilution of the product that
is not bacteriostatic or fungistatic, except for products to be tested
by membrane filtration. The volume of inhibitors or neutralizers of
[[Page 74]]
preservatives added should be considered in determining the proper ratio
of inoculum/medium. Vessels of the product-medium mixture(s) and control
vessels of the medium shall be inoculated with dilutions of cultures of
bacteria or fungi which are viable in the product being tested, and
incubated at the appropriate temperature for no less than 7 days.
(f) Membrane filtration. Bulk and final container material or
products containing oil products in water-insoluble ointments may be
tested for sterility using the membrane filtration procedure set forth
in the United States Pharmacopeia (23d Revision, 1995), section entitled
``Test Procedures Using Membrane Filtration,'' pp. 1689 to 1690, which
is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1
CFR part 51. Copies are available from the United States Pharmacopeial
Convention, Inc., 12601 Twinbrook Pkwy., Rockville, MD 20852, or
available for inspection at the Center for Drug Evaluation and
Research's Division of Medical Library, 5600 Fishers Lane, rm. 11B-40,
Rockville, MD, or at the National Archives and Records Administration
(NARA). (For information on the availability of this material at NARA,
call 202-741-6030, or go to: http://www.archives.gov/federal--register/
code--of--federal--regulations/ibr--locations.html). Except that:
(1) The test samples shall conform with paragraph (d) of this
section; and
(2) In addition, for products containing a mercurial preservative,
the product shall be tested in a second test using Fluid Thioglycollate
Medium incubated at 20 to 25\1/2\C in lieu of the test in Soybean-Casein
Digest Medium.
(g) Exceptions. Bulk and final container material shall be tested
for sterility as described above in this section, except as follows:
(1) Different sterility tests prescribed. When different sterility
tests are prescribed for a product in this subchapter.
(2) Alternate incubation temperatures. Two tests may be performed as
prescribed in paragraph (a)(1)(i) of this section, one test using an
incubation temperature of 18 to 22 [deg]C, the other test using an
incubation temperature of 30 to 37 [deg]C, in lieu of performing one
test using an incubation temperature of 30 to 35 [deg]C, provided that
growth-promoting quality tests have been performed at these
temperatures.
(3) [Reserved]
(4) Test precluded or not required. (i) The tests prescribed in this
section need not be performed for Whole Blood, Cryoprecipitated AHF,
Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine,
Reagent Red Blood Cells, Anti-Human Globulin, or Blood Grouping Reagent.
(ii) Where a manufacturer submits data which the Director, Center
for Biologics Evaluation and Research or the Director, Center for Drug
Evaluation and Research, finds adequate to establish that the mode of
administration, the method of preparation, or the special nature of the
product precludes or does not require a sterility test or that the
sterility of the lot is not necessary to assure the safety, purity, and
potency of the product, the Director may exempt a product from the
sterility requirements of this section subject to any conditions
necessary to assure the safety, purity, and potency of the product.
(5) Number of final containers more than 20, less than 200. If the
number of final containers in the filling is more than 20 or less than
200, the sample shall be no less than 10 percent of the containers.
(6) Number of final containers--20 or less. If the number of final
containers in a filling is 20 or less, the sample shall be two final
containers, or the sample need be no more than one final container,
provided (i) the bulk material met the sterility test requirements and
(ii) after filling, it is demonstrated by testing a simulated sample
that all surfaces to which the product was exposed were free of
contaminating microorganisms. The simulated sample shall be prepared by
rinsing the filling equipment with sterile 1.0 percent peptone solution,
pH 7.1 0.1, which shall be discharged into a final
container by the same method used for filling the final containers with
the product.
(7) Samples--large volume of product in final containers. For
Albumin (Human) and Plasma Protein Fraction (Human), when the volume of
product in the final container is 50 milliliters or more, the
[[Page 75]]
final containers selected as the test sample may contain less than the
full volume of product in the final containers of the filling from which
the sample is taken: Provided, That the containers and closures of the
sample are identical with those used for the filling to which the test
applies, and the sample represents all stages of that filling.
(8) Diagnostic biological products not intended for injection. For
diagnostic biological products not intended for injection, (i) only the
Fluid Thioglycollate Medium test incubated at 30 to 35 [deg]C is
required, (ii) the volume of material for the bulk test shall be no less
than 2.0 milliliters, and (iii) the sample for the final container test
shall be no less than three final containers if the total number filled
is 100 or less, and, if greater, one additional container for each
additional 50 containers or fraction thereof, but the sample need be no
more than 10 containers.
(9) Immune globulin preparations. For immune globulin preparations,
the test samples from the bulk material and from each final container
need be no more than 2.0 ml.
(h) Records. The records related to the testing requirements of this
section shall be prepared and maintained as required by Sec. Sec.
211.167 and 211.194 of this chapter.
[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 41
FR 10428, Mar. 11, 1976; 44 FR 11754, Mar. 2, 1979; 49 FR 15187, Apr.
18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR
44906, Dec. 15, 1986; 53 FR 12764, Apr. 19, 1988; 55 FR 11013, Mar. 26,
1990; 62 FR 48175, Sept. 15, 1997; 67 FR 9587, Mar. 4, 2002; 69 FR
18803, Apr. 9, 2004; 70 FR 14985, Mar. 24, 2005]
Sec. 610.13 Purity.
Products shall be free of extraneous material except that which is
unavoidable in the manufacturing process described in the approved
biologics license application. In addition, products shall be tested as
provided in paragraphs (a) and (b) of this section.
(a)(1) Test for residual moisture. Each lot of dried product shall
be tested for residual moisture and shall meet and not exceed
established limits as specified by an approved method on file in the
biologics license application. The test for residual moisture may be
exempted by the Director, Center for Biologics Evaluation and Research
or the Director, Center for Drug Evaluation and Research, when deemed
not necessary for the continued safety, purity, and potency of the
product.
(2) Records. Appropriate records for residual moisture under
paragraph (a)(1) of this section shall be prepared and maintained as
required by the applicable provisions of Sec. Sec. 211.188 and 211.194
of this chapter.
(b) Test for pyrogenic substances. Each lot of final containers of
any product intended for use by injection shall be tested for pyrogenic
substances by intravenous injection into rabbits as provided in
paragraphs (b) (1) and (2) of this section: Provided, That
notwithstanding any other provision of Subchapter F of this chapter, the
test for pyrogenic substances is not required for the following
products: Products containing formed blood elements; Cryoprecipitate;
Plasma; Source Plasma; Normal Horse Serum; bacterial, viral, and
rickettsial vaccines and antigens; toxoids; toxins; allergenic extracts;
venoms; diagnostic substances and trivalent organic arsenicals.
(1) Test dose. The test dose for each rabbit shall be at least 3
milliliters per kilogram of body weight of the rabbit and also shall be
at least equivalent proportionately, on a body weight basis, to the
maximum single human dose recommended, but need not exceed 10
milliliters per kilogram of body weight of the rabbit, except that: (i)
Regardless of the human dose recommended, the test dose per kilogram of
body weight of each rabbit shall be at least 1 milliliter for immune
globulins derived from human blood; (ii) for Streptokinase, the test
dose shall be at least equivalent proportionately, on a body weight
basis, to the maximum single human dose recommended.
(2) Test procedure, results, and interpretation; standards to be
met. The test for pyrogenic substances shall be performed according to
the requirements specified in United States Pharmacopeia XX.
(3) Retest. If the lot fails to meet the test requirements
prescribed in paragraph (b)(2) of this section, the test
[[Page 76]]
may be repeated once using five other rabbits. The temperature rises
recorded for all eight rabbits used in testing shall be included in
determining whether the requirements are met. The lot meets the
requirements for absence of pyrogens if not more than three of the eight
rabbits show individual rises in temperature of 0.6 [deg]C or more, and
if the sum of the eight individual maximum temperature rises does not
exceed 3.7 [deg]C.
[38 FR 32056, Nov. 20, 1973, as amended at 40 FR 29710, July 15, 1975;
41 FR 10429, Mar. 11, 1976; 41 FR 41424, Sept. 22, 1976; 44 FR 40289,
July 10, 1979; 46 FR 62845, Dec. 29, 1981; 49 FR 15187, Apr. 18, 1984;
50 FR 4134, Jan. 29, 1985; 55 FR 28381, July 11, 1990; 64 FR 56453, Oct.
20, 1999; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005]
Sec. 610.14 Identity.
The contents of a final container of each filling of each lot shall
be tested for identity after all labeling operations shall have been
completed. The identity test shall be specific for each product in a
manner that will adequately identify it as the product designated on
final container and package labels and circulars, and distinguish it
from any other product being processed in the same laboratory. Identity
may be established either through the physical or chemical
characteristics of the product, inspection by macroscopic or microscopic
methods, specific cultural tests, or in vitro or in vivo immunological
tests.
Sec. 610.15 Constituent materials.
(a) Ingredients, preservatives, diluents, adjuvants. All ingredients
used in a licensed product, and any diluent provided as an aid in the
administration of the product, shall meet generally accepted standards
of purity and quality. Any preservative used shall be sufficiently
nontoxic so that the amount present in the recommended dose of the
product will not be toxic to the recipient, and in the combination used
it shall not denature the specific substances in the product to result
in a decrease below the minimum acceptable potency within the dating
period when stored at the recommended temperature. Products in multiple-
dose containers shall contain a preservative, except that a preservative
need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral;
viral vaccines labeled for use with the jet injector; dried vaccines
when the accompanying diluent contains a preservative; or to an
Allergenic Product in 50 percent or more volume in volume (v/v)
glycerin. An adjuvant shall not be introduced into a product unless
there is satisfactory evidence that it does not affect adversely the
safety or potency of the product. The amount of aluminum in the
recommended individual dose of a biological product shall not exceed:
(1) 0.85 milligrams if determined by assay;
(2) 1.14 milligrams if determined by calculation on the basis of the
amount of aluminum compound added; or
(3) 1.25 milligrams determined by assay provided that data
demonstrating that the amount of aluminum used is safe and necessary to
produce the intended effect are submitted to and approved by the
Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research (see mailing addresses in Sec.
600.2 of this chapter).
(b) Extraneous protein; cell culture produced vaccines. Extraneous
protein known to be capable of producing allergenic effects in human
subjects shall not be added to a final virus medium of cell culture
produced vaccines intended for injection. If serum is used at any stage,
its calculated concentration in the final medium shall not exceed
1:1,000,000.
(c) Antibiotics. A minimum concentration of antibiotics, other than
penicillin, may be added to the production substrate of viral vaccines.
[38 FR 32056, Nov. 20, 1973, as amended at 46 FR 51903, Oct. 23, 1981;
48 FR 13025, Mar. 29, 1983; 48 FR 37023, Aug. 16, 1983; 49 FR 23834,
June 8, 1984; 50 FR 4134, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55
FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005]
Sec. 610.16 Total solids in serums.
Except as otherwise provided by regulation, no liquid serum or
antitoxin shall contain more than 20 percent total solids.
[[Page 77]]
Sec. 610.17 Permissible combinations.
Licensed products may not be combined with other licensed products
either therapeutic, prophylactic or diagnostic, except as a license is
obtained for the combined product. Licensed products may not be combined
with nonlicensable therapeutic, prophylactic, or diagnostic substances
except as a license is obtained for such combination.
Sec. 610.18 Cultures.
(a) Storage and maintenance. Cultures used in the manufacture of
products shall be stored in a secure and orderly manner, at a
temperature and by a method that will retain the initial characteristics
of the organisms and insure freedom from contamination and
deterioration.
(b) Identity and verification. Each culture shall be clearly
identified as to source strain. A complete identification of the strain
shall be made for each new stock culture preparation. Primary and
subsequent seed lots shall be identified by lot number and date of
preparation. Periodic tests shall be performed as often as necessary to
verify the integrity of the strain characteristics and freedom from
extraneous organisms. Results of all periodic tests for verification of
cultures and determination of freedom from extraneous organisms shall be
recorded and retained.
(c) Cell lines used for manufacturing biological products--(1)
General requirements. Cell lines used for manufacturing biological
products shall be:
(i) Identified by history;
(ii) Described with respect to cytogenetic characteristics and
tumorigenicity;
(iii) Characterized with respect to in vitro growth characteristics
and life potential; and
(iv) Tested for the presence of detectable microbial agents.
(2) Tests. Tests that are necessary to assure the safety, purity,
and potency of a product may be required by the Director, Center for
Biologics Evaluation and Research or the Director, Center for Drug
Evaluation and Research.
(3) Applicability. This paragraph applies to diploid and nondiploid
cell lines. Primary cell cultures that are not subcultivated and primary
cell cultures that are subsequently subcultivated for only a very
limited number of population doublings are not subject to the provisions
of this paragraph (c).
(d) Records. The records appropriate for cultures under this section
shall be prepared and maintained as required by the applicable
provisions of Sec. Sec. 211.188 and 211.194 of this chapter.
[38 FR 32056, Nov. 20, 1973, as amended at 51 FR 44453, Dec. 10, 1986;
55 FR 11013, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar.
24, 2005]
Subpart C_Standard Preparations and Limits of Potency
Sec. 610.20 Standard preparations.
Standard preparations made available by the Center for Biologics
Evaluation and Research shall be applied in testing, as follows:
(a) Potency standards. Potency standards shall be applied in testing
for potency all forms of the following:
Antibodies
Botulism Antitoxin, Type A.
Botulism Antitoxin, Type B.
Botulism Antitoxin, Type E.
Diphtheria Antitoxin.
Histolyticus Antitoxin.
Oedematiens Antitoxin.
Perfringens Antitoxin.
Antipertussis Serum.
Antirabies Serum.
Sordellii Antitoxin.
Staphylococcus Antitoxin.
Tetanus Antitoxin.
Vibrion Septique Antitoxin.
Antigens
Cholera Vaccine, Inaba serotype.
Cholera Vaccine, Ogawa serotype.
Diphtheria Toxin for Schick Test.
Pertussis Vaccine.
Tuberculin, Old.
Tuberculin, Purified Protein Derivative.
Typhoid Vaccine.
Blood Derivative
Thrombin.
(b) Opacity standard. The U.S. Opacity Standard shall be applied in
estimating the bacterial concentration of all bacterial vaccines. The
assigned value of the standard when observed visually is 10 units. The
assigned value of the standard when observed with a photometer is (1) 10
units when the
[[Page 78]]
wavelength of the filter is 530 millimicrons, (2) 10.6 units when the
wavelength of the filter is 650 millimicrons, and (3) 9 units when the
wavelength of the filter is 420 millimicrons.
[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 10429, Mar. 11, 1976;
41 FR 18295, May 3, 1976; 49 FR 23834, June 8, 1984; 55 FR 11013, Mar.
26, 1990]
Sec. 610.21 Limits of potency.
The potency of the following products shall be not less than that
set forth below and products dispensed in the dried state shall
represent liquid products having the stated limitations.
Antibodies
Diphtheria Antitoxin, 500 units per milliliter.
Tetanus Antitoxin, 400 units per milliliter.
Tetanus Immune Globulin (Human), 250 units of tetanus antitoxin per
container.
Antigens
Cholera Vaccine, 8 units each of Inaba and Ogawa serotype antigens per
milliliter.
Pertussis Vaccine, 12 units per total human immunizing dose.
Typhoid Vaccine, 8 units per milliliter.
[41 FR 10429, Mar. 11, 1976, as amended at 41 FR 18295, May 3, 1976; 70
FR 75028, Dec. 19, 2005]
Subpart D_Mycoplasma
Sec. 610.30 Test for Mycoplasma.
Except as provided otherwise in this subchapter, prior to
clarification or filtration in the case of live virus vaccines produced
from in vitro living cell cultures, and prior to inactivation in the
case of inactivated virus vaccines produced from such living cell
cultures, each virus harvest pool and control fluid pool shall be tested
for the presence of Mycoplasma, as follows:
Samples of the virus for this test shall be stored either (1)
between 2 and 8 [deg]C for no longer than 24 hours, or (2) at -20 [deg]C
or lower if stored for longer than 24 hours. The test shall be performed
on samples of the viral harvest pool and on control fluid pool obtained
at the time of viral harvest, as follows: No less than 2.0 ml. of each
sample shall be inoculated in evenly distributed amounts over the
surface of no less than 10 plates of at least two agar media. No less
than 1.0 ml. of sample shall be inoculated into each of four tubes
containing 10 ml. of a semisolid broth medium. The media shall be such
as have been shown to be capable of detecting known Mycoplasma and each
test shall include control cultures of at least two known strains of
Mycoplasma, one of which must be M. pneumoniae. One half of the plates
and two tubes of broth shall be incubated aerobically at 36 [deg]C
1 [deg]C and the remaining plates and tubes shall
be incubated anaerobically at 36 [deg]C 1 [deg]C
in an environment of 5-10 percent CO2 in N2.
Aerobic incubation shall be for a period of no less than 14 days and the
broth in the two tubes shall be tested after 3 days and 14 days, at
which times 0.5 ml. of broth from each of the two tubes shall be
combined and subinoculated on to no less than 4 additional plates and
incubated aerobically. Anaerobic incubation shall be for no less than 14
days and the broth in the two tubes shall be tested after 3 days and 14
days, at which times 0.5 ml. of broth from each of the two tubes shall
be combined and subinoculated onto no less than four additional plates
and incubated anaerobically. All inoculated plates shall be incubated
for no less than 14 days, at which time observation for growth of
Mycoplasma shall be made at a magnification of no less than 300x. If the
Dienes Methylene Blue-Azure dye or an equivalent staining procedure is
used, no less than a one square cm. plug of the agar shall be excised
from the inoculated area and examined for the presence of Mycoplasma.
The presence of the Mycoplasma shall be determined by comparison of the
growth obtained from the test samples with that of the control cultures,
with respect to typical colonial and microscopic morphology. The virus
pool is satisfactory for vaccine manufacture if none of the tests on the
samples show evidence of the presence of Mycoplasma.
[38 FR 32056, Nov. 20, 1973, as amended at 63 FR 16685, Apr. 6, 1998]
Subpart E_Testing Requirements for Communicable Disease Agents
Sec. 610.40 Test requirements.
(a) Human blood and blood components. Except as specified in
paragraphs (c) and (d) of this section, you, an establishment that
collects blood or blood components, must test each donation of human
blood or blood component intended for use in preparing a product,
including donations intended as a component of, or used to prepare, a
medical device, for evidence of infection due to the following
communicable disease agents:
(1) Human immunodeficiency virus, type 1;
[[Page 79]]
(2) Human immunodeficiency virus, type 2;
(3) Hepatitis B virus;
(4) Hepatitis C virus;
(5) Human T-lymphotropic virus, type I; and
(6) Human T-lymphotropic virus, type II.
(b) Testing using one or more approved screening tests. To test for
evidence of infection due to communicable disease agents designated in
paragraph (a) of this section, you must use screening tests that the
Food and Drug Administration (FDA) has approved for such use, in
accordance with the manufacturer's instructions. You must perform one or
more such tests as necessary to reduce adequately and appropriately the
risk of transmission of communicable disease.
(c) Exceptions to testing for allogeneic transfusion or further
manufacturing use--(1) Dedicated donations. (i) You must test donations
of human blood and blood components from a donor whose donations are
dedicated to and used solely by a single identified recipient under
paragraphs (a), (b), and (e) of this section; except that, if the donor
makes multiple donations for a single identified recipient, you may
perform such testing only on the first donation in each 30-day period.
If an untested dedicated donation is made available for any use other
than transfusion to the single, identified recipient, then this
exemption from the testing required under this section no longer
applies.
(ii) Each donation must be labeled as required under Sec. 606.121
of this chapter and with a label entitled ``INTENDED RECIPIENT
INFORMATION LABEL'' containing the name and identifying information of
the recipient. Each donation must also have the following label, as
appropriate:
------------------------------------------------------------------------
Donor Testing Status Label
------------------------------------------------------------------------
Tests negative Label as required under Sec. 606.121
Tested negative within the last ``DONOR TESTED WITHIN THE LAST 30
30 days DAYS''
------------------------------------------------------------------------
(2) Source Plasma. You are not required to test donations of Source
Plasma for evidence of infection due to the communicable disease agents
listed in paragraphs (a)(5) and (a)(6) of this section.
(3) Medical device. (i) You are not required to test donations of
human blood or blood components intended solely as a component of, or
used to prepare, a medical device for evidence of infection due to the
communicable disease agents listed in paragraphs (a)(5) and (a)(6) of
this section unless the final device contains viable leukocytes.
(ii) Donations of human blood and blood components intended solely
as a component of, or used to prepare, a medical device must be labeled
``Caution: For Further Manufacturing Use as a Component of, or to
Prepare, a Medical Device.''
(4) Samples. You are not required to test samples of blood, blood
components, plasma, or sera if used or distributed for clinical
laboratory testing or research purposes and not intended for
administration to humans or in the manufacture of a product.
(d) Autologous donations. You, an establishment that collects human
blood or blood components from autologous donors, or you, an
establishment that is a consignee of a collecting establishment, are not
required to test donations of human blood or blood components from
autologous donors for evidence of infection due to communicable disease
agents listed in paragraph (a) of this section or by a serological test
for syphilis under paragraph (i) of this section, except:
(1) If you allow any autologous donation to be used for allogeneic
transfusion, you must assure that all autologous donations are tested
under this section.
(2) If you ship autologous donations to another establishment that
allows autologous donations to be used for allogeneic transfusion, you
must assure that all autologous donations shipped to that establishment
are tested under this section.
(3) If you ship autologous donations to another establishment that
does not allow autologous donations to be used for allogeneic
transfusion, you must assure that, at a minimum, the first donation in
each 30-day period is tested under this section.
(4) Each autologous donation must be labeled as required under Sec.
606.121 of
[[Page 80]]
this chapter and with the following label, as appropriate:
------------------------------------------------------------------------
Donor Testing Status Label
------------------------------------------------------------------------
Untested ``DONOR UNTESTED''
Tests negative Label as required under Sec. 606.121
Reactive on current collection/ ``BIOHAZARD'' legend in Sec.
reactive in the last 30 days 610.40(h)(2)(ii)(B)
Tested negative within the last ``DONOR TESTED WITHIN THE LAST 30
30 days DAYS''
------------------------------------------------------------------------
(e) Further testing. You must further test each donation, including
autologous donations, found to be reactive by a screening test performed
under paragraphs (a) and (b) of this section, whenever a supplemental
(additional, more specific) test has been approved for such use by FDA,
except:
(1) For autologous donations, you must further test under this
paragraph, at a minimum, the first reactive donation in each 30-day
period; or
(2) If you have a record for that donor of a positive result on a
supplemental (additional, more specific) test approved for such use by
FDA, you do not have to further test an autologous donation.
(f) Testing responsibility. Required testing under this section,
must be performed by a laboratory registered in accordance with part 607
of this chapter and either certified to perform such testing on human
specimens under the Clinical Laboratory Improvement Amendments of 1988
(42 U.S.C. 263a) under 42 CFR part 493 or has met equivalent
requirements as determined by the Health Care Financing Administration
in accordance with those provisions.
(g) Release or shipment prior to testing. Human blood or blood
components that are required to be tested for evidence of infection due
to communicable disease agents designated in paragraphs (a) and (i) of
this section may be released or shipped prior to completion of testing
in the following circumstances provided that you label the blood or
blood components under Sec. 606.121(h) of this chapter, you complete
the tests for evidence of infection due to communicable disease agents
as soon as possible after release or shipment, and that you provide the
results promptly to the consignee:
(1) Only in appropriately documented medical emergency situations;
or
(2) For further manufacturing use as approved in writing by FDA.
(h) Restrictions on shipment or use--(1) Reactive screening test.
You must not ship or use human blood or blood components that have a
reactive screening test for evidence of infection due to a communicable
disease agent(s) designated in paragraphs (a) and (i) of this section or
that are collected from a donor with a previous record of a reactive
screening test for evidence of infection due to a communicable disease
agent(s) designated in paragraphs (a) and (i) of this section, except as
provided in paragraphs (h)(2)(i) through (h)(2)(vii) of this section.
(2) Exceptions. (i) You may ship or use blood or blood components
intended for autologous use, including reactive donations, as described
in paragraph (d) of this section.
(ii) You must not ship or use human blood or blood components that
have a reactive screening test for evidence of infection due to a
communicable disease agent(s) designated in paragraph (a) of this
section or that are collected from a donor deferred under Sec.
610.41(a) unless you meet the following conditions:
(A) Except for autologous donations, you must obtain from FDA
written approval for the shipment or use;
(B) You must appropriately label such blood or blood components as
required under Sec. 606.121, or Sec. 640.70 of this chapter, and with
the ``BIOHAZARD'' legend;
[GRAPHIC] [TIFF OMITTED] TR11JN01.000
(C) Except for autologous donations, you must label such human blood
and blood components as reactive for the appropriate screening test for
evidence of infection due to the identified communicable disease
agent(s);
(D) If the blood or blood components are intended for further
manufacturing
[[Page 81]]
use into injectable products, you must include a statement on the
container label indicating the exempted use specifically approved by
FDA.
(E) Each blood or blood component with a reactive screening test and
intended solely as a component of, or used to prepare a medical device,
must be labeled with the following label, as appropriate:
------------------------------------------------------------------------
Type of Medical Device Label
------------------------------------------------------------------------
A medical device other than an ``Caution: For Further Manufacturing
in vitro diagnostic reagent Use as a Component of a Medical
Device For Which There Are No
Alternative Sources''
An in vitro diagnostic reagent ``Caution: For Further Manufacturing
Into In Vitro Diagnostic Reagents For
Which There Are No Alternative
Sources''
------------------------------------------------------------------------
(iii) The restrictions on shipment or use do not apply to samples of
blood, blood components, plasma, or sera if used or distributed for
clinical laboratory testing or research purposes, and not intended for
administration in humans or in the manufacture of a product.
(iv) You may use human blood or blood components from a donor with a
previous record of a reactive screening test(s) for evidence of
infection due to a communicable disease agent(s) designated in paragraph
(a) of this section, if:
(A) At the time of donation, the donor is shown or was previously
shown to be suitable by a requalification method or process found
acceptable for such purposes by FDA under Sec. 610.41(b); and
(B) tests performed under paragraphs (a) and (b) of this section are
nonreactive.
(v) Anti-HBc reactive donations, otherwise nonreactive when tested
as required under this section, may be used for further manufacturing
into plasma derivatives without prior FDA approval or a ``BIOHAZARD''
legend as required under paragraphs (h)(2)(ii)(A) and (h)(2)(ii)(B) of
this section.
(vi) You may use human blood or blood components, excluding Source
Plasma, that test reactive by a screening test for syphilis as required
under paragraph (i) of this section if, consistent with Sec. 640.5 of
this chapter, the donation is further tested by an adequate and
appropriate test which demonstrates that the reactive screening test is
a biological false positive. You must label the blood or blood
components with both test results.
(vii) You may use Source Plasma from a donor who tests reactive by a
screening test for syphilis as required under Sec. 610.40(i) of this
chapter, if the donor meets the requirements of Sec. 640.65(b)(2) of
this chapter.
(i) Syphilis testing. In addition to the testing otherwise required
under this section, you must test by a serological test for syphilis
under Sec. Sec. 640.5(a), 640.14, 640.23(a), 640.33(a), 640.53(a), and
640.65(b)(2) of this chapter.
[66 FR 31162, June 11, 2001]
Sec. 610.41 Donor deferral.
(a) You, an establishment that collects human blood or blood
components, must defer donors testing reactive by a screening test for
evidence of infection due to a communicable disease agent(s) listed in
Sec. 610.40(a) or reactive for a serological test for syphilis under
Sec. 610.40(i), from future donations of human blood and blood
components, except:
(1) You are not required to defer a donor who tests reactive for
anti-HBc or anti-HTLV, types I or II, on only one occasion. When a
supplemental (additional, more specific) test for anti-HBc or anti-HTLV,
types I and II, has been approved for use under Sec. 610.40(e) by FDA,
such a donor must be deferred;
(2) A deferred donor who tests reactive for evidence of infection
due to a communicable disease agent(s) listed in Sec. 610.40(a) may
serve as a donor for blood or blood components shipped or used under
Sec. 610.40(h)(2)(ii);
(3) A deferred donor who showed evidence of infection due to
hepatitis B surface antigen (HBsAg) when previously tested under Sec.
610.40(a), (b), and (e) subsequently may donate Source Plasma for use in
the preparation of Hepatitis B Immune Globulin (Human) provided the
current donation tests nonreactive for HBsAg and the donor is otherwise
determined to be suitable;
(4) A deferred donor, who otherwise is determined to be suitable for
donation and tests reactive for anti-HBc or for evidence of infection
due to HTLV, types I and II, may serve as a donor of Source Plasma;
[[Page 82]]
(5) A deferred donor who tests reactive for a communicable disease
agent(s) described under Sec. 610.40(a) or reactive with a serological
test for syphilis under Sec. 610.40(i), may serve as an autologous
donor under Sec. 610.40(d).
(b) A deferred donor subsequently may be found to be suitable as a
donor of blood or blood components by a requalification method or
process found acceptable for such purposes by FDA. Such a donor is
considered no longer deferred.
(c) You must comply with the requirements under Sec. Sec. 610.46
and 610.47 when a donor tests reactive by a screening test for HIV or
HCV required under Sec. 610.40(a) and (b), or when you are aware of
other reliable test results or information indicating evidence of HIV or
HCV infection.
[66 FR 31164, June 11, 2001, as amended at 72 FR 48798, Aug. 24, 2007]
Sec. 610.42 Restrictions on use for further manufacture of medical devices.
(a) In addition to labeling requirements in subchapter H of this
chapter, when a medical device contains human blood or a blood component
as a component of the final device, and the human blood or blood
component was found to be reactive by a screening test performed under
Sec. 610.40(a) and (b) or reactive for syphilis under Sec. 610.40(i),
then you must include in the device labeling a statement of warning
indicating that the product was manufactured from a donation found to be
reactive by a screening test for evidence of infection due to the
identified communicable disease agent(s).
(b) FDA may approve an exception or alternative to the statement of
warning required in paragraph (a) of this section based on evidence that
the reactivity of the human blood or blood component in the medical
device presents no significant health risk through use of the medical
device.
[66 FR 31164, June 11, 2001]
Sec. 610.44 Use of reference panels by manufacturers of test kits.
(a) When available and appropriate to verify acceptable sensitivity
and specificity, you, a manufacturer of test kits, must use a reference
panel you obtain from FDA or from an FDA designated source to test lots
of the following products. You must test each lot of the following
products, unless FDA informs you that less frequent testing is
appropriate, based on your consistent prior production of products of
acceptable sensitivity and specificity:
(1) A test kit approved for use in testing donations of human blood
and blood components for evidence of infection due to communicable
disease agents listed in Sec. 610.40(a); and
(2) Human immunodeficiency virus (HIV) test kit approved for use in
the diagnosis, prognosis, or monitoring of this communicable disease
agent.
(b) You must not distribute a lot that is found to be not acceptable
for sensitivity and specificity under Sec. 610.44(a). FDA may approve
an exception or alternative to this requirement. Applicants must submit
such requests in writing. However, in limited circumstances, such
requests may be made orally and permission may be given orally by FDA.
Oral requests and approvals must be promptly followed by written
requests and written approvals.
[66 FR 31164, June 11, 2001]
Sec. 610.46 Human immunodeficiency virus (HIV) ``lookback'' requirements.
(a) If you are an establishment that collects Whole Blood or blood
components, including Source Plasma and Source Leukocytes, you must
establish, maintain, and follow an appropriate system for the following
actions:
(1) Within 3 calendar days after a donor tests reactive for evidence
of human immunodeficiency virus (HIV) infection when tested under Sec.
610.40(a) and (b) or when you are made aware of other reliable test
results or information indicating evidence of HIV infection, you must
review all records required under Sec. 606.160(d) of this chapter, to
identify blood and blood components previously donated by such a donor.
For those identified blood and blood components collected:
(i) Twelve months and less before the donor's most recent
nonreactive screening tests, or
[[Page 83]]
(ii) Twelve months and less before the donor's reactive direct viral
detection test, e.g., nucleic acid test or HIV p24 antigen test, and
nonreactive antibody screening test, whichever is the lesser period, you
must:
(A) Quarantine all previously collected in-date blood and blood
components identified under paragraph (a)(1) of this section if intended
for use in another person or for further manufacture into injectable
products, except pooled blood components intended solely for further
manufacturing into products that are manufactured using validated viral
clearance procedures; and
(B) Notify consignees to quarantine all previously collected in-date
blood and blood components identified under paragraph (a)(1) of this
section if intended for use in another person or for further manufacture
into injectable products, except pooled blood components intended solely
for further manufacturing into products that are manufactured using
validated viral clearance procedures;
(2) You must perform a supplemental (additional, more specific) test
for HIV as required under Sec. 610.40(e) of this chapter on the
reactive donation.
(3) You must notify consignees of the supplemental (additional, more
specific) test results for HIV, or the results of the reactive screening
test if there is no available supplemental test that is approved for
such use by FDA, or if under an investigational new drug application
(IND) or investigational device exemption (IDE), is exempted for such
use by FDA, within 45 calendar days after the donor tests reactive for
evidence of HIV infection under Sec. 610.40(a) and (b) of this chapter.
Notification of consignees must include the test results for blood and
blood components identified under paragraph (a)(1) of this section that
were previously collected from donors who later test reactive for
evidence of HIV infection.
(4) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components, consistent with the
results of the supplemental (additional, more specific) test performed
under paragraph (a)(2) of this section or the results of the reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an IND or IDE, exempted for
such use by FDA.
(b) If you are a consignee of Whole Blood or blood components,
including Source Plasma and Source Leukocytes, you must establish,
maintain, and follow an appropriate system for the following actions:
(1) You must quarantine all previously collected in-date blood and
blood components identified under paragraph (a)(1) of this section,
except pooled blood components intended solely for further manufacturing
into products that are manufactured using validated viral clearance
procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components consistent with the
results of the supplemental (additional, more specific) test performed
under paragraph (a)(2) of this section, or the results of the reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an IND or IDE, is exempted for
such use by FDA.
(3) When the supplemental (additional, more specific) test for HIV
is positive or when the screening test is reactive and there is no
available supplemental test that is approved for such use by FDA, or if
under an IND or IDE is exempted for such use by FDA, you must notify
transfusion recipients of previous collections of blood and blood
components at increased risk of transmitting HIV infection, or the
recipient's physician of record, of the need for recipient HIV testing
and counseling. You must notify the recipient's physician of record or a
legal representative or relative if the recipient is a minor, deceased,
adjudged incompetent by a State court, or, if the recipient is competent
but State law permits a legal representative or relative to receive
information on behalf of the recipient. You must make reasonable
attempts to perform the notification within 12 weeks after receiving the
supplemental (additional, more specific) test results for evidence of
HIV infection from the collecting establishment, or after receiving the
donor's reactive
[[Page 84]]
screening test result for HIV if there is no available supplemental test
that is approved for such use by FDA, or if under an IND or IDE is
exempted for such use by FDA.
(c) Actions under this section do not constitute a recall as defined
in Sec. 7.3 of this chapter.
[72 FR 48799, Aug. 24, 2007]
Sec. 610.47 Hepatitis C virus (HCV) ``lookback'' requirements.
(a) If you are an establishment that collects Whole Blood or blood
components, including Source Plasma and Source Leukocytes, you must
establish, maintain, and follow an appropriate system for the following
actions:
(1) Within 3 calendar days after a donor tests reactive for evidence
of hepatitis C virus (HCV) infection when tested under Sec. 610.40(a)
and (b) of this chapter or when you are made aware of other reliable
test results or information indicating evidence of HCV infection, you
must review all records required under Sec. 606.160(d) of this chapter,
to identify blood and blood components previously donated by such a
donor. For those identified blood and blood components collected:
(i) Twelve months and less before the donor's most recent
nonreactive screening tests, or
(ii) Twelve months and less before the donor's reactive direct viral
detection test, e.g., nucleic acid test and nonreactive antibody
screening test, whichever is the lesser period, you must:
(A) Quarantine all previously collected in-date blood and blood
components identified under paragraph (a)(1) of this section if intended
for use in another person or for further manufacture into injectable
products, except pooled blood components intended solely for further
manufacturing into products that are manufactured using validated viral
clearance procedures; and
(B) Notify consignees to quarantine all previously collected in-date
blood and blood components identified under paragraph (a)(1) of this
section if intended for use in another person or for further manufacture
into injectable products, except pooled blood components intended solely
for further manufacturing into products that are manufactured using
validated viral clearance procedures;
(2) You must perform a supplemental (additional, more specific) test
for HCV as required under Sec. 610.40(e) on the reactive donation.
(3) You must notify consignees of the supplemental (additional, more
specific) test results for HCV, or the results of the reactive screening
test if there is no available supplemental test that is approved for
such use by FDA, or if under an investigational new drug application
(IND) or investigational device exemption (IDE), is exempted for such
use by FDA, within 45 calendar days after the donor tests reactive for
evidence of HCV infection under Sec. 610.40(a) and (b). Notification of
consignees must include the test results for blood and blood components
identified under paragraph (a)(1) of this section that were previously
collected from donors who later test reactive for evidence of HCV
infection.
(4) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components consistent with the
results of the supplemental (additional, more specific) test performed
under paragraph (a)(2) of this section, or the results of the reactive
screening test if there is no available supplemental test that is
approved for such use by FDA, or if under an IND or IDE, exempted for
such use by FDA.
(b) If you are a consignee of Whole Blood or blood components,
including Source Plasma or Source Leukocytes, you must establish,
maintain, and follow an appropriate system for the following actions:
(1) You must quarantine all previously collected in-date blood and
blood components identified under paragraph (a)(1) of this section,
except pooled blood components intended solely for further manufacturing
into products that are manufactured using validated viral clearance
procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components, consistent with the
results of the supplemental (additional, more specific) test performed
under paragraph (a)(2)
[[Page 85]]
of this section, or the results of the reactive screening test if there
is no available supplemental test that is approved for such use by FDA,
or if under an IND or IDE, is exempted for such use by FDA.
(3) When the supplemental (additional, more specific) test for HCV
is positive or when the screening test is reactive and there is no
available supplemental test that is approved for such use by FDA, or if
under an IND or IDE, is exempted for such use by FDA, you must notify
transfusion recipients of previous collections of blood and blood
components at increased risk of transmitting HCV infection, or the
recipient's physician of record, of the need for recipient HCV testing
and counseling. You must notify the recipient's physician of record or a
legal representative or relative if the recipient is a minor, adjudged
incompetent by a State court, or if the recipient is competent but State
law permits a legal representative or relative to receive information on
behalf of the recipient. You must make reasonable attempts to perform
the notification within 12 weeks after receiving the supplemental
(additional, more specific) test results for evidence of HCV infection
from the collecting establishment, or after receiving the donor's
reactive screening test result for HCV if there is no available
supplemental test that is approved for such use by FDA, or if under an
IND or IDE, is exempted for such use by FDA.
(c) Actions under this section do not constitute a recall as defined
in Sec. 7.3 of this chapter.
[72 FR 48799, Aug. 24, 2007]
Sec. 610.48 Hepatitis C virus (HCV) ``lookback'' requirements based on
review of historical testing records.
(a) Establishments that collect Whole Blood or blood components,
including Source Plasma and Source Leukocytes, must complete the
following actions by February 19, 2009.
(b) If you are an establishment that collects Whole Blood or blood
components, including Source Plasma and Source Leukocytes, you must
establish, maintain, and follow an appropriate system for the following
actions:
(1) You must:
(i) Review all records of donor testing for hepatitis C virus (HCV)
performed before February 20, 2008. The review must include records
dating back indefinitely for computerized electronic records, and to
January 1, 1988, for all other records. Record review, quarantine,
testing, notification, and disposition performed before February 20,
2008 that otherwise satisfy the requirements under Sec. 610.47, are
exempt from this section.
(ii) Identify donors who tested reactive for evidence of HCV
infection. Donors who tested reactive by a screening test and negative
by an appropriate supplemental (additional, more specific) test under
Sec. 610.40(e) for evidence of HCV infection on the same donation are
not subject to further action.
(iii) Identify the blood and blood components previously collected
from such donors:
(A) Twelve months and less before the donor's most recent
nonreactive screening tests, or
(B) Twelve months and less before the donor's reactive direct viral
detection test, e.g., nucleic acid test and nonreactive antibody
screening test, whichever is the lesser period.
(2) If you did not perform a supplemental (additional, more
specific) test at the time of the reactive donation, you may perform a
supplemental test or a licensed screening test with known greater
sensitivity than the test of record using either a frozen sample from
the same reactive donation or a fresh sample from the same donor, if
obtainable. If neither is available, proceed with paragraphs (b)(3),
(b)(4), and (b)(5) of this section.
(3) You must, within 3 calendar days after identifying the blood and
blood components previously collected from donors who tested reactive
for evidence of HCV infection:
(i) Quarantine all previously collected in-date blood and blood
components identified under paragraph (b)(1)(iii) of this section if
intended for use in another person or for further manufacture into
injectable products, except pooled components solely intended for
further manufacturing into products that are manufactured using
validated viral clearance procedures.
[[Page 86]]
(ii) Notify consignees to quarantine all previously collected in-
date blood and blood components identified under paragraph (b)(1)(iii)
of this section if intended for use in another person or for further
manufacture into injectable products, except pooled blood components
intended solely for further manufacturing into products that are
manufactured using validated viral clearance procedures; and
(iii) Notify consignees of the donor's test results, including the
results of a supplemental (additional, more specific) test or a licensed
screening test with known greater sensitivity than the test of record,
if available at that time.
(4) You must notify consignees of the results of the supplemental
(additional, more specific) test or the licensed screening test with
known greater sensitivity than the test of record for HCV, if performed,
within 45 calendar days of completing the further testing. Notification
of consignees must include the test results for blood and blood
components identified under paragraph (b)(1)(iii) of this section that
were previously collected from a donor who later tests reactive for
evidence of HCV infection.
(5) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components consistent with the
results of the further testing performed under paragraph (b)(2) of this
section or the results of the reactive screening test if there is no
available supplemental test that is approved for such use by FDA, or if
under an investigational new drug application (IND) or investigational
device exemption (IDE), is exempted for such use by FDA.
(c) If you are a consignee of Whole Blood or blood components,
including Source Plasma and Source Leukocytes, you must establish,
maintain, and follow an appropriate system for the following actions,
which you must complete within 1 year of the date of notification by the
collecting establishment:
(1) You must quarantine all previously collected in-date blood and
blood components identified under paragraph (b)(1)(iii) of this section,
except pooled blood components solely intended for further manufacturing
into products that are manufactured using validated viral clearance
procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel
quarantined in-date blood and blood components, consistent with the
results of the further testing performed under paragraph (b)(2) of this
section, or the results of the reactive screening test if there is no
available supplemental test that is approved for such use by FDA, or if
under an IND or IDE is exempted for such use by FDA.
(3) When the supplemental (additional, more specific) test for HCV
is positive; or the supplemental test is indeterminate, but the
supplemental test is known to be less sensitive than the screening test;
or the screening test is reactive and there is no available supplemental
test that is approved for such use by FDA, or if under an IND or IDE, is
exempted for such use by FDA; or if supplemental testing is not
performed, you must make reasonable attempts to notify transfusion
recipients of previous collections of blood and blood components at
increased risk of transmitting HCV infection, or the recipient's
physician of record, of the need for recipient HCV testing and
counseling. You must notify the recipient's physician of record or a
legal representative or relative if the recipient is a minor, adjudged
incompetent by a State court, or if the recipient is competent but State
law permits a legal representative or relative to receive information on
behalf of the recipient.
(d) Actions under this section do not constitute a recall as defined
in Sec. 7.3 of this chapter.
(e) This section will expire on August 24, 2015.
[72 FR 48800, Aug. 24, 2007]
Subpart F_Dating Period Limitations
Sec. 610.50 Date of manufacture.
The date of manufacture shall be determined as follows:
(a) For products for which an official standard of potency is
prescribed in either Sec. 610.20 or Sec. 610.21, or which are subject
to official potency tests, the date
[[Page 87]]
of initiation by the manufacturer of the last valid potency test.
(b) For products that are not subject to official potency tests, (1)
the date of removal from animals, (2) the date of extraction, (3) the
date of solution, (4) the date of cessation of growth, or (5) the date
of final sterile filtration of a bulk solution, whichever is applicable.
[38 FR 32056, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977]
Sec. 610.53 Dating periods for licensed biological products.
(a) General. The minimum dating periods in paragraph (c) of this
section are based on data relating to usage, clinical experience, or
laboratory tests that establish the reasonable period beyond which the
product cannot be expected to yield its specific results and retain its
safety, purity, and potency, provided the product is maintained at the
recommended temperatures. The standards prescribed by the regulations in
this subchapter are designed to ensure the continued safety, purity, and
potency of the products and are based on the dating periods set forth in
paragraph (c) of this section. Package labels for each product shall
recommend storage at the stated temperatures.
(b) When the dating period begins. The dating period for a product
shall begin on the date of manufacture, as prescribed in Sec. 610.50.
The dating period for a combination of two or more products shall be no
longer than the dating period of the component with the shortest dating
period.
(c) Table of dating periods. In using the table in this paragraph, a
product in column A may be stored by the manufacturer at the prescribed
temperature and length of time in either column B or C, plus the length
of time in column D. The dating period in column D shall be applied from
the day the product leaves the manufacturer's storage, provided the
product has not exceeded its maximum storage period, as prescribed in
column B or C. If a product is held in the manufacturer's storage beyond
the period prescribed, the dating period for the product being
distributed shall be reduced by a corresponding period.
----------------------------------------------------------------------------------------------------------------
A B C D
----------------------------------------------------------------------------------------------------------------
Dating period after
Manufacturer's storage Manufacturer's storage leaving manufacturer's
Product period 1 to 5 [deg]C period 0 [deg]C or storage when stored at 2
(unless otherwise colder (unless to 8 [deg]C (unless
stated) otherwise stated) otherwise stated)
----------------------------------------------------------------------------------------------------------------
Adenovirus Vaccine Live Oral....... 6 months............... Not applicable........ 6 months.
Albumin (Human).................... 3 years................ ......do.............. (a) 5 years.
......do............... ......do.............. (b) 3 years, provided
labeling recommends
storage at room
temperature, no warmer
than 37 [deg]C.
Not applicable......... ......do.............. (c) 10 years, if in a
hermetically sealed metal
container and provided
labeling recommends
storage between 2 and 8
[deg]C.
Allergenic Extracts labeled ``No
U.S. Standard of Potency'':
1. With 50 percent or more 3 years................ ......do.............. 3 years.
glycerin.
2. With less than 50 percent 18 months.............. ......do.............. 18 months.
glycerin.
3. Products for which cold Not applicable......... ......do.............. 18 months (from date of
storage conditions are manufacture), provided
inappropriate. labeling recommends
storage at 30 [deg]C or
colder.
4. Powders and tablets......... ......do............... ......do.............. 5 years (from date of
manufacture), provided
labeling recommends
storage at 30 [deg]C or
colder.
5. Freeze-dried products:
a. Unreconstituted........... ......do............... ......do.............. 4 years (from date of
manufacture).
b. Reconstituted............. ......do............... ......do.............. 18 months (cannot exceed 4-
year unreconstituted
dating period plus an
additional 12 months).
Allergenic Extracts, Alum 18 months.............. ......do.............. 18 months.
Precipitated labeled ``No U.S.
Standard of Potency''.
Anthrax Vaccine Adsorbed........... 2 years................ ......do.............. 1 year.
[[Page 88]]
Antibody to Hepatitis B Surface
Antigen:
1. Antibody to Hepatitis B 6 months............... ......do.............. 6 months.
Surface Antigen.
2. Lyophilized coated red blood ......do............... ......do.............. Do.
cells.
3. Enzyme conjugated products.. ......do............... ......do.............. Do.
Iodinated (\125\l) products........ Not applicable......... ......do.............. 45 days (from date of
manufacture).
Antihemophilic Factor (Human)...... ......do............... ......do.............. 1 year (from date of
manufacture).
Anti-Human Globulin Liquid......... ......do............... ......do.............. 2 years.
Anti-Inhibitor Coagulant Complex... ......do............... ......do.............. Do.
Antirabies Serum................... 1 year................. ......do.............. Do.
Antivenin (Crotalidae) Polyvalent.. ......do............... ......do.............. 5 years with an initial 10
percent excess of
potency, provided
labeling recommends
storage at 37 [deg] C or
colder.
Antivenin (Latrodectus Mactans).... ......do............... ......do.............. 5 years with an initial 10
percent excess of
potency.
Antivenin (Micurus fulvius)........ ......do............... ......do.............. Do.
Asparaginase....................... Not applicable......... ......do.............. 18 months from the date of
the last valid potency
test.
BCG Vaccine........................ 1 year................. Not applicable........ 6 months.
Blood Grouping Reagents
1. Liquid...................... Not applicable......... Not applicable........ 2 years.
2. Dried....................... 1 year................. 2 years............... 5 years.
Blood Group Substance AB........... ......do............... ......do.............. 2 years.
Blood Group Substance A............ ......do............... ......do.............. Do.
Blood Group Substance B............ ......do............... ......do.............. Do.
Botulism Antitoxin................. ......do............... Not applicable........ 5 years with an initial 20
percent excess of
potency.
Cholera Vaccine.................... ......do............... ......do.............. 18 months.
Coccidioidin....................... ......do............... ......do.............. 3 years.
Collagenase........................ Not applicable......... ......do.............. 4 years (from date of
manufacture), provided
labeling recommends
storage at 37 [deg]C or
colder.
Cryoprecipitated AHF............... ......do............... ......do.............. 12 months from the date of
collection of source
blood, provided labeling
recommends storage at -18
[deg]C or colder.
Diphtheria Antitoxin:
1. Liquid...................... 1 year................. ......do.............. 5 years with an initial 20
percent excess of
potency.
2. Dried....................... ......do............... 2 years............... 5 years with an initial 10
percent excess of
potency.
Diphtheria and Tetanus Toxoids and ......do............... Not applicable........ 18 months.
Pertussis Vaccine Adsorbed.
Diphtheria and Tetanus Toxoids, ......do............... ......do.............. 2 years.
Adsorbed.
Diphtheria Toxin for Schick Test... ......do............... ......do.............. 1 year.
Diphtheria Toxoid.................. ......do............... ......do.............. 2 years.
Diphtheria Toxoid Adsorbed......... ......do............... 2 years............... Do.
Diphtheria Toxoid-Schick Test Not applicable......... Not applicable........ 1 year.
Control.
Factor IX Complex.................. ......do............... ......do.............. 1 year (from date of
manufacture).
Fibrinolysin (Human)............... 1 year................. 2 years............... 2 years.
Fibrinolysin and Desoxyribonuclease ......do............... ......do.............. 3 years, provided labeling
Combined (Bovine). recommends storage at 30
[deg]C or colder.
Fibrinolysin and Desoxyribonuclease ......do............... ......do.............. Do.
Combined (Bovine) with
Chloramphenicol.
Hepatitis B Surface Antigen:
1. Unlyophilized coated red Not applicable......... ......do.............. 14 days (from date of
blood cells. manufacture).
2. Iodinated (\125\ l) product. ......do............... ......do.............. 45 days (from date of
manufacture).
3. Enzyme conjugated product... 6 months............... ......do.............. 6 months.
Histoplasmin....................... 1 year................. Not applicable........ 2 years.
Immunoglobulins:
1. Hepatitis B Immune Globulin Not applicable......... ......do.............. 1 year.
(Human).
2. Immune Globulin (Human)..... 3 years................ ......do.............. 3 years.
3. Immune Globulin Intravenous Not applicable......... ......do.............. 1 year.
(Human).
[[Page 89]]
4. Lymphocyte Immune Globulin, ......do............... Not applicable........ 2 years.
Anti-Thymocyte Globulin
(Equine).
5. Pertussis Immune Globulin 3 years................ ......do.............. 3 years from date the
(Human). dried or frozen bulk
product is placed in
final solution.
6. Rabies Immune Globulin 1 year................. ......do.............. 1 year.
(Human).
7. Rho(D) Immune Globulin 6 months............... ......do.............. 6 months.
(Human).
8. Tetanus Immune Globulin 1 year................. ......do.............. 3 years with an initial 10
(Human). percent excess of
potency.
9. Vaccinia Immune Globulin 3 years................ ......do.............. 3 years.
(Human).
10. Varicella-Zoster Immune Not applicable......... ......do.............. 1 year.
Globulin (Human).
Hepatitis B Vaccine................ 2 years at 2 to 8 Not applicable........ 3 years.
[deg]C.
Influenza Virus Vaccine............ 1 year................. ......do.............. 18 months.
Limulus Amebocyte Lysate........... Not applicable......... Not applicable........ 18 months (from date of
manufacture).
Measles, Mumps, and Rubella Virus ......do............... 1 year (-20 [deg]C or 1 year.
Vaccine Live. colder).
Measles and Mumps Virus Vaccine ......do............... ......do.............. 1 year.
Live.
Measles and Rubella Virus Vaccine ......do............... ......do.............. Do.
Live.
Measles Live and Smallpox Vaccine.. Not applicable......... ......do.............. 1 year (from date of
manufacture).
Measles Virus Vaccine Live......... ......do............... ......do.............. 1 year.
Meningococcal Polysaccharide
Vaccine Group A:
1. Final bulk powder........... ......do............... 2 years (-20 [deg]C or Not applicable.
colder).
2. Final container............. Not applicable......... 3 years (-20 [deg]C or 2 years.
colder).
Meningococcal Polysaccharide
Vaccine Group C:
1. Final bulk powder........... ......do............... 2 years (-20 [deg]C or Not applicable.
colder).
2. Final container............. ......do............... 3 years (-20 [deg]C or 2 years.
colder).
Meningococcal Polysaccharide
Vaccine Groups A and C combined:
1. Final bulk powder........... ......do............... 2 years (-20 [deg]C or Not applicable.
colder).
2. Final container............. ......do............... 3 years (-20 [deg]C or 2 years.
colder).
Meningococcal Polysaccharide
Vaccine Groups A, C, Y, and W135
combined:
1. Final bulk power............ ......do............... 2 years (-20 [deg]C or Not applicable.
colder).
2. Final container............. ......do............... 3 years (-20 [deg]C or 2 years.
colder).
Mumps Skin Test Antigen............ 6 months............... Not applicable........ 18 months.
Mumps Virus Vaccine Live........... Not applicable......... 1 year (-20 [deg]C or 1 year.
colder).
Normal Horse Serum................. 1 year................. 2 years............... 5 years.
Pertussis Vaccine.................. ......do............... Not applicable........ 18 months.
Pertussis Vaccine Adsorbed......... ......do............... ......do.............. Do.
Plague Vaccine..................... ......do............... ......do.............. Do.
Plasma products:
1. Fresh Frozen Plasma......... Not applicable......... ......do.............. 1 year from date of
collection of source
blood (-18 [deg]C or
colder).
2. Liquid Plasma............... ......do............... ......do.............. (a) 26 days from date of
collection of source
blood (between 1 and 6
[deg]C).
(b) 40 days from date of
collection of source
blood only when CPDA-1
solution is used as the
anticoagulant (between 1
and 6 [deg]C).
3. Plasma...................... ......do............... ......do.............. 5 years from date of
collection of source
blood (-18 [deg]C or
colder).
[[Page 90]]
4. Platelet Rich Plasma........ ......do............... ......do.............. 72 hours from time of
collection of source
blood, provided labeling
recommends storage (20 to
24 [deg]C or between 1
and 6 [deg]C). 5 days if
certain approved
containers are used (20
to 24 [deg]C).
5. Source Leukocytes........... ......do............... ......do.............. In lieu of expiration
date, the collection date
shall appear on the
label.
6. Source Plasma............... ......do............... ......do.............. 10 years (at the
recommended storage
temperature stated on the
label).
7. Therapeutic Exchange Plasma. ......do............... ......do.............. 10 years.
Plasma Protein Fraction (Human).... 1 year................. ......do.............. (a) 5 years.
(b) 3 years provided
labeling recommends
storage at room
temperature, no warmer
than 30 [deg]C).
Platelets.......................... Not applicable......... ......do.............. 72 hours from time of
collection of source
blood, provided labeling
recommends storage at 20
to 24 [deg]C or between 1
and 6 [deg]C, or as
specified in the
directions for use for
the blood collecting,
processing, and storage
system approved for such
use by the Director,
Center for Biologics
Evaluation and Research
(CBER).
Pneumococcal Vaccine Polyvalent:
1. Final bulk powder........... ......do............... 24 months after Not applicable.
potency assay (-20
[deg]C or colder).
2. Final container............. ......do............... Not applicable........ 2 years (from date of
manufacture).
Poliovirus Vaccine Inactivated..... 1 year................. ......do.............. 1 year.
Poliovirus Vaccine Live Oral
Trivalent:
1. Frozen...................... Not applicable......... 1 year (-10 [deg]C or 1 year, provided labeling
colder). recommends storage at a
temperature which will
maintain ice continuously
in a solid state.
2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling
recommends storage
between 2 and 8 [deg]C
and container has been
unopened.
Poliovirus Vaccine Live Oral Type
I:
1. Frozen...................... ......do............... 1 year (-10 [deg]C or 1 year, provided labeling
colder). recommends storage at a
temperature which will
maintain ice continuously
in a solid state.
2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling
recommends storage
between 2 and 8 [deg]C
and container has been
unopened.
Poliovirus Vaccine Live Oral Type
II:
1. Frozen...................... ......do............... 1 year (-10 [deg]C or 1 year, provided labeling
colder). recommends storage at a
temperature which will
maintain ice continuously
in a solid state.
2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling
recommends storage
between 2 and 8 [deg]C
and container has been
unopened.
Poliovirus Vaccine Live Oral Type
III:
1. Frozen...................... ......do............... 1 year (-10 [deg]C or 1 year, provided labeling
colder). recommends storage at a
temperature which will
maintain ice continuously
in a solid state.
2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling
recommends storage
between 2 and 8 [deg]C
and container has been
unopened.
Polyvalent bacterial antigens with 1 year................. ......do.............. 18 months.
``No U.S. Standard of Potency''
liquid.
Polyvalent bacterial vaccines with ......do............... ......do.............. Do.
``No U.S. Standard of Potency''
liquid.
Rabies Vaccine:
1. Dried....................... ......do............... 2 years............... Do.
2. Liquid...................... 3 months............... Not applicable........ 6 months.
[[Page 91]]
Reagent red blood cells............ Not applicable......... Not applicable........ Thirty-five days from
earliest date of
collection if kept in
liquid form (indefinite
storage of reagent red
blood cell source
material at -65 [deg]C or
colder).
ACD Red Blood Cells................ ......do............... ......do.............. (a) 21 days from date of
collection of source
blood, provided labeling
recommends storage
between 1 and 6 [deg]C
and the hermetic seal is
not broken during
processing.
(b) 24 hours after plasma
removal, provided
labeling recommends
storage between 1 and 6
[deg]C and the hermetic
seal is broken during
processing.
CPD Red Blood Cells................ ......do............... ......do.............. (a) 21 days from date of
collection of source
blood, provided labeling
recommends storage
between 1 and 6 [deg]C
and the hermetic seal is
not broken during
processing.
(b) 24 hours after plasma
removal, provided
labeling recommends
storage between 1 and 6
[deg]C and the hermetic
seal is broken during
processing.
CPDA-1 Red Blood Cells............. ......do............... ......do.............. (a) 35 days from date of
collection of source
blood, provided labeling
recommends storage
between 1 and 6 [deg]C
and the hermetic seal is
not broken during
processing.
(b) 24 hours after plasma
removal, provided
labeling recommends
storage between 1 and 6
[deg]C and the hermetic
seal is broken during
processing.
Red Blood Cells Deglycerolized..... ......do............... ......do.............. 24 hours after removal
from storage at -65
[deg]C or colder,
provided labeling
recommends storage
between 1 and 6 [deg]C,
or as specified in the
directions for use for
the blood collecting,
processing, and storage
system approved for such
use by the Director,
CBER.
Red Blood Cells Frozen............. ......do............... ......do.............. 10 years from date of
collection of source
blood, provided labeling
recommends storage at -65
[deg]C or colder, or as
specified in the
directions for use for
the blood collecting,
processing, and storage
system approved for such
use by the Director,
CBER.
Rubella and Mumps Virus Vaccine ......do............... 1 year (-20 [deg]C or 1 year.
Live. colder).
Rubella Virus Vaccine Live......... ......do............... ......do.............. Do.
Skin Test Antigens for Cellular 6 months............... Not applicable........ Do.
Hypersensitivity.
Smallpox Vaccine:
1. Liquid...................... Not applicable......... 9 months (-10 [deg]C 3 months, provided
or colder, if product labeling recommends
is maintained as storage at 0 [deg]C or
glycerinated or colder.
equivalent vaccine in
bulk or final
containers).
2. Dried....................... 6 months............... Not applicable........ 18 months.
Streptokinase...................... Not applicable......... ......do.............. Do.
Tetanus and Diphtheria Toxoids 1 year................. ......do.............. 2 years.
Adsorbed for Adult Use.
Tetanus Antitoxin:
1. Liquid...................... ......do............... ......do.............. 5 years with an initial 20
percent excess or
potency.
2. Dried....................... ......do............... 2 years............... 5 years with an initial 10
percent excess or
potency.
[[Page 92]]
Tetanus Toxoid..................... ......do............... Not applicable........ 2 years.
Tetanus Toxoid Adsorbed............ ......do............... ......do.............. Do.
Thrombin........................... ......do............... 2 year................ 3 years.
Thrombin Impregnated Pad........... Not applicable......... Not applicable........ 1 year, or 6 months at 20
to 24 [deg]C.
Tuberculin:
1. Purified Protein Derivative, 6 months............... ......do.............. 1 year.
diluted.
2. Old or Purified Protein 1 year (not to exceed ......do.............. 2 years, provided labeling
Derivative dried on multiple 30 [deg]C; do not recommends storage at a
puncture device. refrigerate). temperature not to exceed
30 [deg]C. Do not
refrigerate.
3. Old on multiple puncture ......do............... ......do.............. Do.
device.
Typhoid Vaccine.................... 1 year................. ......do.............. 18 months.
ACD Whole Blood.................... Not applicable......... ......do.............. 21 days from date of
collection, provided
labeling recommends
storage between 1 and 6
[deg]C.
CPD Whole Blood.................... ......do............... ......do.............. Do.
CPDA-1 Whole Blood................. ......do............... ......do.............. 35 days from date of
collection, provided
labeling recommends
storage between 1 and 6
[deg]C.
Heparin Whole Blood................ ......do............... ......do.............. 48 hours from date of
collection, provided
labeling recommends
storage between 1 and 6
[deg]C.
Yellow Fever Vaccine............... ......do............... 1 year (-20 [deg]C or 1 year, provided labeling
colder). recommends storage at 5
[deg]C or colder.
----------------------------------------------------------------------------------------------------------------
(d) Exemptions. Exemptions or modifications shall be made only upon
written approval, in the form of a supplement to the biologics license
application, issued by the Director, Center for Biologics Evaluation and
Research or the Director of the Center for Drug Evaluation and Research.
[50 FR 4134, Jan. 29, 1985, as amended at 51 FR 15607, Apr. 25, 1986; 51
FR 19750, June 2, 1986; 52 FR 37450, Oct. 7, 1987; 53 FR 12764, Apr. 19,
1988; 62 FR 15110, Mar. 31, 1997; 64 FR 56453, Oct. 20, 1999; 70 FR
14985, Mar. 24, 2005; 72 FR 45887, Aug. 16, 2007; 72 FR 54208, Sept. 24,
2007; 73 FR 49942, Aug. 25, 2008]
Subpart G_Labeling Standards
Sec. 610.60 Container label.
(a) Full label. The following items shall appear on the label
affixed to each container of a product capable of bearing a full label:
(1) The proper name of the product;
(2) The name, address, and license number of manufacturer;
(3) The lot number or other lot identification;
(4) The expiration date;
(5) The recommended individual dose, for multiple dose containers.
(6) The statement: `` `Rx only' '' for prescription biologicals.
(7) If a Medication Guide is required under part 208 of this
chapter, the statement required under Sec. 208.24(d) of this chapter
instructing the authorized dispenser to provide a Medication Guide to
each patient to whom the drug is dispensed and stating how the
Medication Guide is provided, except where the container label is too
small, the required statement may be placed on the package label.
(b) Package label information. If the container is not enclosed in a
package, all the items required for a package label shall appear on the
container label.
(c) Partial label. If the container is capable of bearing only a
partial label, the container shall show as a minimum the name (expressed
either as the proper or common name), the lot number or other lot
identification and the name of the manufacturer; in addition, for
multiple dose containers, the recommended individual dose. Containers
bearing partial labels shall be placed in a package which bears all the
items required for a package label.
[[Page 93]]
(d) No container label. If the container is incapable of bearing any
label, the items required for a container label may be omitted, provided
the container is placed in a package which bears all the items required
for a package label.
(e) Visual inspection. When the label has been affixed to the
container a sufficient area of the container shall remain uncovered for
its full length or circumference to permit inspection of the contents.
[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 63
FR 66400, Dec. 1, 1998; 67 FR 4907, Feb. 1, 2002]
Sec. 610.61 Package label.
The following items shall appear on the label affixed to each
package containing a product:
(a) The proper name of the product;
(b) The name, address, and license number of manufacturer;
(c) The lot number or other lot identification;
(d) The expiration date;
(e) The preservative used and its concentration, or if no
preservative is used and the absence of a preservative is a safety
factor, the words ``no preservative'';
(f) The number of containers, if more than one;
(g) The amount of product in the container expressed as (1) the
number of doses, (2) volume, (3) units of potency, (4) weight, (5)
equivalent volume (for dried product to be reconstituted), or (6) such
combination of the foregoing as needed for an accurate description of
the contents, whichever is applicable;
(h) The recommended storage temperature;
(i) The words ``Shake Well'', ``Do not Freeze'' or the equivalent,
as well as other instructions, when indicated by the character of the
product;
(j) The recommended individual dose if the enclosed container(s) is
a multiple-dose container;
(k) The route of administration recommended, or reference to such
directions in an enclosed circular;
(l) Known sensitizing substances, or reference to an enclosed
circular containing appropriate information;
(m) The type and calculated amount of antibiotics added during
manufacture;
(n) The inactive ingredients when a safety factor, or reference to
an enclosed circular containing appropriate information;
(o) The adjuvant, if present;
(p) The source of the product when a factor in safe administration;
(q) The identity of each microorganism used in manufacture, and,
where applicable, the production medium and the method of inactivation,
or reference to an enclosed circular containing appropriate information;
(r) Minimum potency of product expressed in terms of official
standard of potency or, if potency is a factor and no U.S. standard of
potency has been prescribed, the words ``No U.S. standard of potency.''
(s) The statement: `` `Rx only' '' for prescription biologicals.
[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 55
FR 10423, Mar. 21, 1990; 67 FR 4907, Feb. 1, 2002]
Sec. 610.62 Proper name; package label; legible type.
(a) Position. The proper name of the product on the package label
shall be placed above any trademark or trade name identifying the
product and symmetrically arranged with respect to other printing on the
label.
(b) Prominence. The point size and typeface of the proper name shall
be at least as prominent as the point size and typeface used in
designating the trademark and trade name. The contrast in color value
between the proper name and the background shall be at least as great as
the color value between the trademark and trade name and the background.
Typography, layout, contrast, and other printing features shall not be
used in a manner that will affect adversely the prominence of the proper
name.
(c) Legible type. All items required to be on the container label
and package label shall be in legible type. ``Legible type'' is type of
a size and character which can be read with ease when held in a good
light and with normal vision.
Sec. 610.63 Divided manufacturing responsibility to be shown.
If two or more licensed manufacturers participate in the manufacture
of a biological product, the name, address,
[[Page 94]]
and license number of each must appear on the package label, and on the
label of the container if capable of bearing a full label.
[64 FR 56453, Oct. 20, 1999]
Sec. 610.64 Name and address of distributor.
The name and address of the distributor of a product may appear on
the label provided that the name, address, and license number of the
manufacturer also appears on the label and the name of the distributor
is qualified by one of the following phrases: ``Manufactured for ------
----'', ``Distributed by ------------'', ``Manufactured by ----------
for ----------'', ``Manufactured for ---------- by --------'',
``Distributor: ----------'', or ``Marketed by ----------''. The
qualifying phrases may be abbreviated.
[61 FR 57330, Nov. 6, 1996]
Sec. 610.65 Products for export.
Labels on packages or containers of products for export may be
adapted to meet specific requirements of the regulations of the country
to which the product is to be exported provided that in all such cases
the minimum label requirements prescribed in Sec. 610.60 are observed.
Sec. 610.67 Bar code label requirements.
Biological products must comply with the bar code requirements at
Sec. 201.25 of this chapter. However, the bar code requirements do not
apply to devices regulated by the Center for Biologics Evaluation and
Research or to blood and blood components intended for transfusion. For
blood and blood components intended for transfusion, the requirements at
Sec. 606.121(c)(13) of this chapter apply instead.
[69 FR 9171, Feb. 26, 2004]
Sec. 610.68 Exceptions or alternatives to labeling requirements for
biological products held by the Strategic National Stockpile.
(a) The appropriate FDA Center Director may grant an exception or
alternative to any provision listed in paragraph (f) of this section and
not explicitly required by statute, for specified lots, batches, or
other units of a biological product, if the Center Director determines
that compliance with such labeling requirement could adversely affect
the safety, effectiveness, or availability of such product that is or
will be included in the Strategic National Stockpile.
(b)(1)(i) A Strategic National Stockpile official or any entity that
manufactures (including labeling, packing, relabeling, or repackaging),
distributes, or stores a biological product that is or will be included
in the Strategic National Stockpile may submit, with written concurrence
from a Strategic National Stockpile official, a written request for an
exception or alternative described in paragraph (a) of this section to
the Center Director.
(ii) The Center Director may grant an exception or alternative
described in paragraph (a) of this section on his or her own initiative.
(2) A written request for an exception or alternative described in
paragraph (a) of this section must:
(i) Identify the specified lots, batches, or other units of the
biological product that would be subject to the exception or
alternative;
(ii) Identify the labeling provision(s) listed in paragraph (f) of
this section that are the subject of the exception or alternative
request;
(iii) Explain why compliance with such labeling provision(s) could
adversely affect the safety, effectiveness, or availability of the
specified lots, batches, or other units of the biological product that
are or will be included in the Strategic National Stockpile;
(iv) Describe any proposed safeguards or conditions that will be
implemented so that the labeling of the product includes appropriate
information necessary for the safe and effective use of the product,
given the anticipated circumstances of use of the product;
(v) Provide a draft of the proposed labeling of the specified lots,
batches, or other units of the biological product subject to the
exception or alternative; and
(vi) Provide any other information requested by the Center Director
in support of the request.
[[Page 95]]
(c) The Center Director must respond in writing to all requests
under this section.
(d) A grant of an exception or alternative under this section will
include any safeguards or conditions deemed appropriate by the Center
Director so that the labeling of product subject to the exception or
alternative includes the information necessary for the safe and
effective use of the product, given the anticipated circumstances of
use.
(e) If you are a sponsor receiving a grant of a request for an
exception or alternative to the labeling requirements under this
section:
(1) You need not submit a supplement under Sec. 601.12(f)(1)
through (f)(2) of this chapter; however,
(2) You must report any grant of a request for an exception or
alternative under this section as part of your annual report under Sec.
601.12(f)(3) of this chapter.
(f) The Center Director may grant an exception or alternative under
this section to the following provisions of this chapter, to the extent
that the requirements in these provisions are not explicitly required by
statute:
(1) Sec. 610.60;
(2) Sec. 610.61(c) and (e) through (r);
(3) Sec. 610.62;
(4) Sec. 610.63;
(5) Sec. 610.64;
(6) Sec. 610.65; and
(7) Sec. 312.6.
[72 FR 73600, Dec. 28, 2007]
PART 630_GENERAL REQUIREMENTS FOR BLOOD, BLOOD COMPONENTS, AND BLOOD
DERIVATIVES--Table of Contents
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371; 42 U.S.C.
216, 262, 264.
Source: 66 FR 31176, June 11, 2001, unless otherwise noted.
Sec. 630.6 Donor notification.
(a) Notification of donors. You, an establishment that collects
blood or blood components, must make reasonable attempts to notify any
donor, including an autologous donor, who has been deferred based on the
results of tests for evidence of infection with a communicable disease
agent(s) as required by Sec. 610.41 of this chapter; or who has been
determined not to be suitable as a donor based on suitability criteria
under Sec. 640.3 or Sec. 640.63 of this chapter. You must attempt to
obtain the results of supplemental testing required under Sec.
610.40(e) of this chapter prior to notifying a donor of the deferral. If
notification occurs prior to receipt of such results, you must also
notify a deferred donor of the results of the supplemental testing. You
must notify a donor as described in paragraph (b) of this section.
(b) Content of notification. You must provide the following
information to a donor deferred or determined not to be suitable as a
donor as described in paragraph (a) of this section:
(1) That the donor is deferred or determined not to be suitable for
donation and the reason for that decision;
(2) Where appropriate, the types of donation of blood or blood
components that the donor should not donate in the future;
(3) Where applicable, the results of tests for evidence of infection
due to communicable disease agent(s) that were a basis for deferral
under Sec. 610.41 of this chapter, including results of supplemental
(i.e., additional, more specific) tests as required in Sec. 610.40(e)
of this chapter; and,
(4) Where appropriate, information concerning medical followup and
counseling.
(c) Time period for notification. You must make reasonable attempts
to notify the donor within 8 weeks after determining that the donor is
deferred or determined not to be suitable for donation as described in
paragraph (a) of this section. You must document that you have
successfully notified the donor or when you are unsuccessful that you
have made reasonable attempts to notify the donor.
(d) Autologous donors. (1) You also must provide the following
information to the referring physician of an autologous donor who is
deferred based on the results of tests for evidence of infection with a
communicable disease agent(s) as described in paragraph (a) of this
section:
(i) Information that the autologous donor is deferred based on the
results of tests for evidence of infection due to
[[Page 96]]
communicable disease agent(s), as required under Sec. 610.41 of this
chapter, and the reason for that decision;
(ii) Where appropriate, the types of donation of blood or blood
components that the autologous donor should not donate in the future;
and
(iii) The results of tests for evidence of infection due to
communicable disease agent(s), that were a basis for deferral under
Sec. 610.41 of this chapter, including results of supplemental (i.e.,
additional, more specific) tests as required in Sec. 610.40(e) of this
chapter.
(2) You must make reasonable attempts to notify the autologous
donor's referring physician within 8 weeks after determining that the
autologous donor is deferred as described in paragraph (a) of this
section. You must document that you have successfully notified the
autologous donor's referring physician or when you are unsuccessful that
you have made reasonable attempts to notify the physician.
PART 640_ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS--Table of
Contents
Subpart A_Whole Blood
Sec.
640.1 Whole Blood.
640.2 General requirements.
640.3 Suitability of donor.
640.4 Collection of the blood.
640.5 Testing the blood.
640.6 Modifications of Whole Blood.
Subpart B_Red Blood Cells
640.10 Red Blood Cells.
640.11 General requirements.
640.12 Suitability of donor.
640.13 Collection of the blood.
640.14 Testing the blood.
640.15 Segments for testing.
640.16 Processing.
640.17 Modifications for specific products.
Subpart C_Platelets
640.20 Platelets.
640.21 Suitability of donors.
640.22 Collection of source material.
640.23 Testing the blood.
640.24 Processing.
640.25 General requirements.
640.27 Emergency provisions.
Subpart D_Plasma
640.30 Plasma.
640.31 Suitability of donors.
640.32 Collection of source material.
640.33 Testing the blood.
640.34 Processing.
Subpart E [Reserved]
Subpart F_Cryoprecipitate
640.50 Cryoprecipitate AHF.
640.51 Suitability of donors.
640.52 Collection of source material.
640.53 Testing the blood.
640.54 Processing.
640.55 U.S. Standard preparation.
640.56 Quality control test for potency.
Subpart G_Source Plasma
640.60 Source Plasma.
640.61 Informed consent.
640.62 Medical supervision.
640.63 Suitability of donor.
640.64 Collection of blood for Source Plasma.
640.65 Plasmapheresis.
640.66 Immunization of donors.
640.67 Laboratory tests.
640.68 Processing.
640.69 General requirements.
640.70 Labeling.
640.71 Manufacturing responsibility.
640.72 Records.
640.73 Reporting of fatal donor reactions.
640.74 Modification of Source Plasma.
640.76 Products stored or shipped at unacceptable temperatures.
Subpart H_Albumin (Human)
640.80 Albumin (Human).
640.81 Processing.
640.82 Tests on final product.
640.83 General requirements.
640.84 Labeling.
Subpart I_Plasma Protein Fraction (Human)
640.90 Plasma Protein Fraction (Human).
640.91 Processing.
640.92 Tests on final product.
640.93 General requirements.
640.94 Labeling.
Subpart J_Immune Globulin (Human)
640.100 Immune Globulin (Human).
640.101 General requirements.
640.102 Manufacture of Immune Globulin (Human).
640.103 The final product.
640.104 Potency.
Subpart K [Reserved]
[[Page 97]]
Subpart L_Alternative Procedures
640.120 Alternative procedures.
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C.
216, 262, 263, 263a, 264.
Source: 38 FR 32089, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A_Whole Blood
Sec. 640.1 Whole Blood.
The proper name of this product shall be Whole Blood. Whole Blood is
defined as blood collected from human donors for transfusion to human
recipients.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]
Sec. 640.2 General requirements.
(a) Manufacturing responsibility. All manufacturing of Whole Blood,
including donor examination, blood collection, laboratory tests,
labeling, storage and issue, shall be done under the supervision and
control of the same licensed establishment except that the Director,
Center for Biologics Evaluation and Research, may approve arrangements,
upon joint request of two or more licensed establishments, which he
finds are of such a nature as to assure compliance otherwise with the
provisions of this subchapter.
(b) Blood container. The blood container shall not be entered prior
to issue for any purpose except for blood collection or when the method
of processing requires use of a different container. The container shall
be uncolored and transparent to permit visual inspection of the contents
and any closure shall be such as will maintain a hermetic seal and
prevent contamination of the contents. The container material shall not
interact with the contents under the customary conditions of storage and
use, in such a manner as to have an adverse effect upon the safety,
purity, or potency of the blood.
(c) Reissue of blood. Blood that has been removed from storage
controlled by a licensed establishment shall not be reissued by a
licensed establishment unless the following conditions are observed:
(1) The container has a tamper-proof seal when originally issued and
this seal remains unbroken;
(2) A segment is properly attached and has not been removed, except
that blood lacking a properly attached segment may be reissued in an
emergency provided it is accompanied by instructions for sampling and
for use within 6 hours after entering the container for sampling;
(3) The blood has been stored continuously at 1 to 6 [deg]C and
shipped between 1 and 10 [deg]C;
(4) The blood is held for observation until a significant inspection
consistent with the requirements of Sec. 640.5(e) can be made.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 42
FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 15187, Apr.
18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 53 FR
116, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6,
1998; 64 FR 45371, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR
31165, June 11, 2001; 66 FR 40889, Aug. 6, 2001; 67 FR 9587, Mar. 4,
2002]
Sec. 640.3 Suitability of donor.
(a) Method of determining. The suitability of a donor as a source of
Whole Blood shall be determined by a qualified physician or by persons
under his supervision and trained in determining suitability. Such
determination shall be made on the day of collection from the donor by
means of medical history, a test for hemoglobin level, and such physical
examination as appears necessary to a physician who shall be present on
the premises when examinations are made, except that the suitability of
donors may be determined when a physician is not present on the
premises, provided the establishment (1) maintains on the premises, and
files with the Center for Biologics Evaluation and Research, a manual of
standard procedures and methods, approved by the Director of the Center
for Biologics Evaluation and Research, that shall be followed by
employees who determine suitability of donors, and (2) maintains records
indicating the name
[[Page 98]]
and qualifications of the person immediately in charge of the employees
who determine the suitability of donors when a physician is not present
on the premises.
(b) Qualifications of donor; general. Except as provided in
paragraph (f) of this section and for autologous donations, a person may
not serve as a source of Whole Blood more than once in 8 weeks. In
addition, donors shall be in good health, as indicated in part by:
(1) Normal temperature;
(2) Demonstration that systolic and diastolic blood pressures are
within normal limits, unless the examining physician is satisfied that
an individual with blood pressures outside these limits is an otherwise
qualified donor under the provisions of this section;
(3) For allogeneic donors, a blood hemoglobin level which shall be
demonstrated to be no less than 12.5 grams (g) of hemoglobin per 100
milliliters (mL) of blood; or a hematocrit value of 38 percent, and for
autologous donors, a blood hemoglobin level which shall be demonstrated
to be no less than 11.0 g of hemoglobin per 100 mL of blood or a
hematocrit value of 33 percent.
(4) Freedom from acute respiratory diseases;
(5) Freedom from any infectious skin disease at the site of
phlebotomy and from any such disease generalized to such an extent as to
create a risk of contamination of the blood;
(6) Freedom from any disease transmissible by blood transfusion,
insofar as can be determined by history and examinations indicated
above; and
(7) Freedom of the arms and forearms from skin punctures or scars
indicative of addiction to self-injected narcotics.
(c) Additional qualifications of donor; viral hepatitis. No
individual shall be used as a source of Whole Blood if he has--
(1) A history of viral hepatitis after the 11th birthday;
(2) A history of close contact within 12 months of donation with an
individual having viral hepatitis;
(3) A history of having received within 12 months of donation, human
blood or any derivative of human blood which the Food and Drug
Administration has advised the blood establishment is a possible source
of viral hepatitis.
(d) Therapeutic bleedings. Blood withdrawn in order to promote the
health of a donor otherwise qualified under the provisions of this
section, shall not be used as a source of Whole Blood unless the
container label conspicuously indicates the donor's disease that
necessitated withdrawal of blood.
(e) [Reserved]
(f) Qualifications; donations within less than 8 weeks. A person may
serve as a source of Whole Blood more than once in 8 weeks only if at
the time of donation the person is examined and certified by a physician
to be in good health, as indicated in part in paragraph (b) of this
section.
[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50
FR 4138, Jan. 29, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar.
26, 1990; 64 FR 45371, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR
40889, Aug. 6, 2001]
Sec. 640.4 Collection of the blood.
(a) Supervision. Blood shall be drawn from the donor by a qualified
physician or under his supervision by assistants trained in the
procedure. A physician shall be present on the premises when blood is
being collected, except that blood may be collected when a physician is
not present on the premises, provided the establishment (1) maintains on
the premises, and files with the Center for Biologics Evaluation and
Research, a manual of standard procedures and methods, approved by the
Director of the Center for Biologics Evaluation and Research, that shall
be followed by employees who collect blood, and (2) maintains records
indicating the name and qualifications of the person immediately in
charge of the employees who collect blood when a physician is not
present on the premises.
(b) The donor center. The pertinent requirements of Sec. Sec.
600.10 and 600.11 of this chapter shall apply at both the blood
establishment and at any other place where the bleeding is performed.
(c) Blood containers. Blood containers and donor sets shall be
pyrogen-free, sterile and identified by lot number. The amount of
anticoagulant required for the quantity of blood to be collected shall
be in the blood container
[[Page 99]]
when it is sterilized. In addition, all container and donor set surfaces
that come in contact with blood used in the processing of Heparin Whole
Blood shall be water repellent.
(d) The anticoagulant solution. The anticoagulant solution shall be
sterile and pyrogen-free. Anticoagulant solutions shall be compounded
and used according to a formula approved by the Director, Center for
Biologics Evaluation and Research.
(e) Donor identification. Each unit of blood shall be so marked or
identified by number or other symbol as to relate it to the individual
donor whose identity shall be established to the extent necessary for
compliance with Sec. 640.3.
(f) Prevention of contamination of the blood. The skin of the donor
at the site of phlebotomy shall be prepared thoroughly and carefully by
a method that gives maximum assurance of a sterile container of blood.
The blood shall be collected by aseptic methods in a sterile system
which may be closed or may be vented if the vent protects the blood
against contamination.
(g) Samples and segments for laboratory tests. Samples and segments
for laboratory tests shall meet the following standards:
(1) One or more segments shall be provided with each unit of blood
when issued or reissued except as provided in Sec. 640.2(c)(2) and all
segments shall be from the donor who is the source of the unit of blood.
(2) All samples for laboratory tests performed by the manufacturer
and all segments accompanying a unit of blood shall be collected at the
time of filling the original blood container.
(3) All containers for all samples shall bear the donor's
identification before collecting the samples.
(4) All segments accompanying a unit of blood shall be attached to
the whole blood container before blood collection, in a tamperproof
manner that will conspicuously indicate removal and reattachment.
(5) Segments for compatibility testing shall contain blood mixed
with the appropriate anticoagulant.
(h) Storage. Whole Blood must be placed in storage at a temperature
between 1 and 6 [deg]C immediately after collection unless the blood is
to be further processed into another component or the blood must be
transported from the donor center to the processing laboratory. If
transported, the blood must be placed in temporary storage having
sufficient refrigeration capacity to cool the blood continuously toward
a temperature range between 1 and 10 [deg]C until arrival at the
processing laboratory. At the processing laboratory, the blood must be
stored at a temperature between 1 and 6 [deg]C. Blood from which a
component is to be prepared must be held in an environment maintained at
a temperature range specified for that component in the directions for
use for the blood collecting, processing, and storage system approved
for such use by the Director, CBER.
[38 FR 32089, Nov. 20, 1973, as amended at 42 FR 59878, Nov. 22, 1977;
43 FR 34460, Aug. 4, 1978; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan.
29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45372, Aug. 19, 1999; 66 FR
1836, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001; 72 FR 45887, Aug. 16,
2007; 73 FR 7464, Feb. 8, 2008]
Sec. 640.5 Testing the blood.
All laboratory tests shall be made on a specimen of blood taken from
the donor at the time of collecting the unit of blood, and these tests
shall include the following:
(a) Serological test for syphilis. Whole Blood shall be negative to
a serological test for syphilis.
(b) Determination of blood group. Each container of Whole Blood
shall be classified as to ABO blood group. At least two blood group
tests shall be made and the unit shall not be issued until grouping
tests by different methods or with different lots of antiserums are in
agreement. Only those Anti-A and Anti-B Blood Grouping Reagents licensed
under, or that otherwise meet the requirements of, the regulations of
this subchapter shall be used, and the technique used shall be that for
which the serum is specifically designed to be effective.
(c) Determination of the Rh factors. Each container of Whole Blood
shall be classified as to Rh type on the basis of tests done on the
sample. The label shall indicate the extent of typing and the results of
all tests performed. If the test, using Anti-D Blood Grouping Reagent,
is positive, the container may be
[[Page 100]]
labeled ``Rh Positive.'' If the test is negative, the results shall be
confirmed by further testing which shall include tests for the ``weak D
(formerly D\u\).'' Blood may be labeled ``Rh Negative'' if further
testing is negative. Units testing positive after additional more
specific testing shall be labeled as ``Rh Positive.'' Only Anti-Rh Blood
Grouping Reagents licensed under, or that otherwise meet the
requirements of, this subchapter shall be used, and the technique used
shall be that for which the reagent is specifically designed to be
effective.
(d) Sterility test. Whole Blood intended for transfusion shall not
be tested for sterility by a method that entails entering the final
container before the blood is used for transfusion.
(e) Inspection. Whole Blood shall be inspected visually during
storage and immediately prior to issue. If the color or physical
appearance is abnormal or there is any indication or suspicion of
microbial contamination the unit of Whole Blood shall not be issued for
transfusion.
(f) Test for communicable disease agents. Whole Blood shall be
tested for evidence of infection due to communicable disease agents as
required under Sec. 610.40 of this chapter.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985; 53
FR 117, Jan. 5, 1988; 53 FR 12764, Apr. 19, 1988; 64 FR 45372, Aug. 19,
1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 66 FR
40889, Aug. 6, 2001]
Sec. 640.6 Modifications of Whole Blood.
Upon approval by the Director, Center for Biologics Evaluation and
Research, of a supplement to the biologics license application for Whole
Blood a manufacturer may prepare Whole Blood from which the
antihemophilic factor has been removed, provided the Whole Blood meets
the applicable requirements of this subchapter and the following
conditions are met:
(a) The antihemophilic factor shall be removed in accordance with
paragraphs (a), (b), and (c) of Sec. 640.52.
(b) Although the closed system between the red blood cells and
plasma shall be maintained, the red blood cells shall be maintained
between 1 and 6[deg] C at all times, including that time when the plasma
is being frozen for removal of the antihemophilic factor.
[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50
FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept.
28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999]
Subpart B_Red Blood Cells
Sec. 640.10 Red Blood Cells.
The proper name of this product shall be Red Blood Cells. The
product is defined as red blood cells remaining after separating plasma
from human blood.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]
Sec. 640.11 General requirements.
(a) Storage. Immediately after processing, the Red Blood Cells shall
be placed in storage and maintained at a temperature between 1 and 6
[deg]C.
(b) Inspection. The product shall be inspected immediately after
separation of the plasma, periodically during storage, and at the time
of issue. The product shall not be issued if there is any abnormality in
color or physical appearance or if there is any indication of microbial
contamination.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 42
FR 59878, Nov. 11, 1977; 50 FR 4139, Jan. 29, 1985]
Sec. 640.12 Suitability of donor.
The source blood for Red Blood Cells shall be obtained from a donor
who meets the criteria for donor suitability prescribed in Sec. 640.3.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985]
Sec. 640.13 Collection of the blood.
(a) The source blood shall be collected as prescribed in Sec.
640.4.
(b) Source blood may also be derived from Whole Blood manufactured
in accordance with applicable provisions of this subchapter.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985; 64
FR 45372, Aug. 19, 1999]
Sec. 640.14 Testing the blood.
Blood from which Red Blood Cells are prepared shall be tested as
prescribed
[[Page 101]]
in Sec. 610.40 of this chapter and Sec. 640.5 (a), (b), and (c).
[53 FR 117, Jan. 5, 1988, as amended at 66 FR 31165, June 11, 2001]
Sec. 640.15 Segments for testing.
Segments collected in integral tubing shall meet the following
standards:
(a) One or more segments shall be provided with each unit of Whole
Blood or Red Blood Cells when issued or reissued.
(b) Before they are filled, all segments shall be marked or
identified so as to relate them to the donor of that unit of red cells.
(c) All segments accompanying a unit of Red Blood Cells shall be
filled at the time the blood is collected or at the time the final
product is prepared.
[66 FR 40890, Aug. 6, 2001]
Sec. 640.16 Processing.
(a) Separation. Within the timeframe specified in the directions for
use for the blood collecting, processing, and storage system used, Red
Blood Cells may be prepared either by centrifugation, done in a manner
that will not tend to increase the temperature of the blood, or by
normal undisturbed sedimentation. A portion of the plasma sufficient to
insure optimal cell preservation shall be left with the red cells except
when a cryoprotective substance or additive solution is added for
prolonged storage.
(b) Sterile system. All surfaces that come in contact with the red
cells shall be sterile and pyrogen-free.
(c) Final containers. Final containers used for Red Blood Cells
shall be the original blood containers unless the method of processing
requires a different container. The final container shall meet the
requirements for blood containers prescribed in Sec. 640.2(c). At the
time of filing, if a different container is used, it shall be marked or
identified by number or other symbol so as to relate it to the donor of
that unit of red cells.
[38 FR 32089, Nov. 20, 1973, as amended at 43 FR 34460, Aug. 4, 1978; 50
FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10,
2001; 66 FR 40890, Aug. 6, 2001]
Sec. 640.17 Modifications for specific products.
Red Blood Cells Frozen: A cryophylactic substance may be added to
the Red Blood Cells for extended manufacturers' storage at -65[deg] C or
colder, provided the manufacturer submits data considered by the
Director, Center for Biologics Evaluation and Research, as adequately
demonstrating through in vivo cell survival and other appropriate tests
that the addition of the substance, the materials used and the
processing methods results in a final product that meets the required
standards of safety, purity, and potency for Red Blood Cells, and that
the frozen product will maintain those properties for the prescribed
dating period. Section 640.11 (a) and (b) do not apply while a
cryophylactic substance is present.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 49
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990; 63 FR 16685, Apr. 6, 1998]
Subpart C_Platelets
Sec. 640.20 Platelets.
(a) Proper name and definition. The proper name of this product
shall be Platelets. The product is defined as platelets collected from
one unit of blood and resuspended in an appropriate volume of original
plasma, as prescribed in Sec. 640.24(d).
(b) Source. The source material for Platelets is plasma which may be
obtained by whole blood collection or by plateletpheresis.
[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 50
FR 4139, Jan. 29, 1985; 72 FR 45887, Aug. 16, 2007]
Sec. 640.21 Suitability of donors.
(a) Whole blood donors shall meet the criteria for suitability
prescribed in Sec. 640.3.
(b) [Reserved]
(c) Plateletpheresis donors must meet the criteria for suitability
as prescribed in Sec. Sec. 640.3 and 640.63(c)(6) or as described in an
approved biologics license application (BLA) or an approved
[[Page 102]]
supplement to a BLA. Informed consent must be obtained as prescribed in
Sec. 640.61.
[40 FR 4304, Jan. 29, 1975, as amended at 49 FR 23834, June 8, 1984; 64
FR 56453, Oct. 20, 1999; 72 FR 45887, Aug. 16, 2007]
Sec. 640.22 Collection of source material.
(a) Whole blood used as the source of Platelets shall be collected
as prescribed in Sec. 640.4.
(b) [Reserved]
(c) If plateletpheresis is used, the procedure for collection must
be as prescribed in Sec. Sec. 640.62, 640.64 (except paragraph (c)),
and 640.65, or as described in an approved biologics license application
(BLA) or an approved supplement to a BLA.
(d) The phlebotomy shall be performed by a single uninterrupted
venipuncture with minimal damage to, and minimal manipulation of, the
donor's tissue.
[40 FR 4304, Jan. 29, 1975, as amended at 45 FR 27927, Apr. 25, 1980; 49
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990; 59 FR 49351, Sept. 28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR
56453, Oct. 20, 1999; 72 FR 45887, Aug. 16, 2007]
Sec. 640.23 Testing the blood.
(a) Blood from which plasma is separated for the preparation of
Platelets shall be tested as prescribed in Sec. 610.40 of this chapter
and Sec. 640.5 (a), (b), and (c).
(b) The tests shall be performed on a sample of blood collected at
the time of collecting the source blood, and such sample container shall
be labeled with the donor's number before the container is filled.
[40 FR 4304, Jan. 29, 1975, as amended at 50 FR 4139, Jan. 29, 1985; 53
FR 117, Jan. 5, 1988; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10,
2001; 66 FR 31165, June 11, 2001]
Sec. 640.24 Processing.
(a) Separation of plasma and platelets and resuspension of the
platelets must be in a closed system. Platelets must not be pooled
during processing unless the platelets are pooled as specified in the
directions for use for the blood collecting, processing, and storage
system approved for such use by the Director, Center for Biologics
Evaluation and Research.
(b) Immediately after collection, the whole blood or plasma shall be
held in storage between 20 and 24 [deg]C unless it must be transported
from the collection center to the processing laboratory. During such
transport, all reasonable methods shall be used to maintain the
temperature as close as possible to a range between 20 and 24 [deg]C
until it arrives at the processing laboratory where it shall be held
between 20 and 24 [deg]C until the platelets are separated. The platelet
concentrate shall be separated within 4 hours or within the timeframe
specified in the directions for use for the blood collecting,
processing, and storage system.
(c) The time and speed of centrifugation must have been demonstrated
to produce an unclumped product, without visible hemolysis, that yields
a count of not less than 5.5x10\10\ platelets per unit in at least 75
percent of the units tested.
(d) The volume of original plasma used for resuspension of the
platelets shall be determined by the maintenance of a pH of not less
than 6.2 during the storage period. The pH shall be measured on a sample
of platelets which has been stored for the maximum dating period at the
selected storage temperature. One of the following storage temperatures
shall be used continuously:
(1) 20 to 24 [deg]C.
(2) 1 to 6 [deg]C.
(e) Final containers used for Platelets shall be colorless and
transparent to permit visual inspection of the contents; any closure
shall maintain a hermetic seal and prevent contamination of the
contents. The container material shall not interact with the contents,
under the customary conditions of storage and use, in such a manner as
to have an adverse effect upon the safety, purity, potency, or efficacy
of the product. At the time of filling, the final container shall be
marked or identified by number so as to relate it to the donor.
[40 FR 4304, Jan. 29, 1975, as amended at 42 FR 10983, Feb. 25, 1977; 47
FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985; 63 FR 16685, Apr. 6,
1998; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR
40890, Aug. 6, 2001; 72 FR 45887, Aug. 16, 2007; 73 FR 7464, Feb. 8,
2008]
[[Page 103]]
Sec. 640.25 General requirements.
(a) Storage. Immediately after resuspension, Platelets shall be
placed in storage at the selected temperature range. If stored at 20 to
24 [deg]C, a continuous gentle agitation of the platelet concentrate
shall be maintained throughout the storage period. Agitation is optional
if stored at a temperature between 1 and 6 [deg]C.
(b) Quality control testing. Each month four units prepared from
different donors shall be tested at the end of the storage period as
follows:
(1) Platelet count.
(2) pH of not less than 6.2 measured at the storage temperature of
the unit.
(3) Measurement of actual plasma volume.
(4) If the results of the quality control testing indicate that the
product does not meet the prescribed requirements, immediate corrective
action shall be taken and a record maintained of such action.
(c) Manufacturing responsibility. All manufacturing of Platelets
shall be performed at the same licensed establishment, except that the
quality control testing under paragraph (b) of this section may be
performed by a clinical laboratory which meets the standards of the
Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C.
263a) and is qualified to perform platelet counts. Such arrangements
must be approved by the Director, Center for Biologics Evaluation and
Research, Food and Drug Administration. Such testing shall not be
considered as divided manufacturing, as described in Sec. 610.63 of
this chapter, provided the following conditions are met:
(1) The results of each test are received within 10 days of the
preparation of the platelet concentrate, and are maintained by the
establishment licensed for Platelets so that they may be reviewed by an
authorized representative of the Food and Drug Administration.
(2) The licensed Platelets manufacturer has obtained a written
agreement that the testing laboratory will permit an authorized
representative of the Food and Drug Administration to inspect its
testing procedures and facilities during reasonable business hours.
(3) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 49
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990; 66 FR 1836, Jan. 10, 2001; 72 FR 45888, Aug. 16, 2007]
Sec. 640.27 Emergency provisions.
The use of the plateletpheresis procedure to obtain a product for a
specific recipient may be at variance with Sec. Sec. 640.21(c) and
640.22(c): Provided, That: (a) A licensed physician has determined that
the recipient must be transfused with the platelets from a specific
donor, and (b) the plateletpheresis procedure is performed under the
supervision of a qualified licensed physician who is aware of the health
status of the donor and the physician has certified in writing that the
donor's health permits plateletpheresis.
[40 FR 53544, Nov. 18, 1975]
Subpart D_Plasma
Sec. 640.30 Plasma.
(a) Proper name and definition. The proper name of this component is
Plasma. The component is defined as:
(1) The fluid portion of one unit of human blood intended for
intravenous use which is collected in a closed system, stabilized
against clotting, and separated from the red cells; or
(2) The fluid portion of human blood intended for intravenous use
which is prepared by apheresis methods as specified in the directions
for use for the blood collecting, processing, and storage system
including closed and open systems.
(b) Source. (1) Plasma shall be obtained by separating plasma from
blood collected from blood donors or by plasmapheresis.
(2) Plasma may be obtained from a unit of Whole Blood collected by
another licensed establishment.
[42 FR 59878, Nov. 22, 1977; 48 FR 13026, Mar. 29, 1983, as amended at
50 FR 4139, Jan. 29, 1985; 72 FR 45888, Aug. 16, 2007]
[[Page 104]]
Sec. 640.31 Suitability of donors.
(a) Whole blood donors shall meet the criteria for donor suitability
prescribed in Sec. 640.3.
(b) Plasmapheresis donors shall meet the criteria for donor
suitability prescribed in Sec. 640.63, excluding the phrase ``other
than malaria'' in paragraph (c)(9) of that section. Informed consent
shall be required as prescribed in Sec. 640.61.
[42 FR 59878, Nov. 22, 1977, as amended at 64 FR 45372, Aug. 19, 1999]
Sec. 640.32 Collection of source material.
(a) Whole Blood must be collected, transported, and stored as
prescribed in Sec. 640.4. When whole blood is intended for Plasma,
Fresh Frozen Plasma, and Liquid Plasma, until the plasma is removed, the
whole blood must be maintained at a temperature between 1 and 6 [deg]C
or as specified in the directions for use for the blood collecting,
processing, and storage system approved for such use by the Director,
Center for Biologics Evaluations and Research. Whole blood intended for
Platelet Rich Plasma must be maintained as prescribed in Sec. 640.24
until the plasma is removed. The red blood cells must be placed in
storage at a temperature between 1 and 6 [deg]C immediately after the
plasma is separated.
(b) Plasma obtained by plasmapheresis shall be collected as
prescribed in Sec. Sec. 640.62, 640.64 (except that paragraph (c)(3) of
Sec. 640.64 shall not apply), and Sec. 640.65.
[42 FR 59878, Nov. 22, 1977, as amended at 45 FR 27927, Apr. 25, 1980;
50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 72 FR 45888, Aug.
16, 2007]
Sec. 640.33 Testing the blood.
(a) Blood from which plasma is separated shall be tested as
prescribed in Sec. 610.40 of this chapter and Sec. 640.5 (a), (b), and
(c).
(b) Manufacturers of Plasma collected by plasmapheresis shall have
testing and recordkeeping responsibilities equivalent to those
prescribed in Sec. Sec. 640.71 and 640.72.
[42 FR 59878, Nov. 22, 1977, as amended at 44 FR 17658, Mar. 23, 1979;
50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 66 FR 31165, June
11, 2001]
Sec. 640.34 Processing.
(a) Plasma. Plasma shall be separated from the red blood cells and
shall be stored at -18 [deg]C or colder within 6 hours after transfer to
the final container or within the timeframe specified in the directions
for use for the blood collecting, processing, and storage system unless
the product is to be stored as Liquid Plasma.
(b) Fresh Frozen Plasma. Fresh frozen plasma shall be prepared from
blood collected by a single uninterrupted venipuncture with minimal
damage to and minimal manipulation of the donor's tissue. The plasma
must be separated from the red blood cells or collected by an apheresis
procedure, and placed in a freezer within 8 hours or within the
timeframe specified in the directions for use for the blood collecting,
processing, and storage system, and stored at -18 [deg]C or colder.
(c) Liquid Plasma. Liquid Plasma shall be separated from the red
blood cells and shall be stored at a temperature of 1 to 6 [deg]C within
4 hours after filling the final container or within the timeframe
specified in the directions for use for the blood collecting,
processing, and storage system.
(d) Platelet Rich Plasma. Platelet rich plasma shall be prepared
from blood collected by a single uninterrupted venipuncture with minimal
damage to and manipulation of the donor's tissue. The plasma shall be
separated from the red blood cells by centrifugation within 4 hours
after completion of the phlebotomy or within the timeframe specified in
the directions for use for the blood collecting, processing, and storage
system. The time and speed of the centrifugation shall have been shown
to produce a product with at least 250,000 platelets per microliter. The
plasma shall be stored at a temperature between 20 and 24 [deg]C
immediately after filling the final container. A gentle and continuous
agitation of the product shall be maintained throughout the storage
period, if stored at a temperature of 20 to 24 [deg]C.
(e) Modifications of Plasma. It is possible to separate Platelets
and/or Cryoprecipitated AHF from Plasma. When these components are to be
separated, the plasma shall be collected as described in Sec. 640.32
for Plasma.
[[Page 105]]
(1) Platelets shall be separated as prescribed in subpart C of part
640, prior to freezing the plasma. The remaining plasma may be labeled
as ``Fresh Frozen Plasma,'' if frozen within 6 hours after filling the
final container or within the timeframe specified in the directions for
use for the blood collecting, processing, and storage system.
(2) Cryoprecipitated AHF shall be removed as prescribed in subpart F
of part 640. The remaining plasma shall be labeled ``Plasma,
Cryoprecipitate Reduced.''
(3) Plasma remaining after both Platelets and Cryoprecipitated AHF
have been removed may be labeled ``Plasma, Cryoprecipitate Reduced.''
(f) The final container. (1) The final container shall have no color
added to the plastic and shall be transparent to permit visual
inspection of the contents; any closure shall maintain a hermetic seal
and prevent contamination of the contents.
(2) The final container material shall not interact with the
contents, under the customary conditions of storage and use, in such a
manner as to have an adverse effect upon the safety, purity, potency,
and effectiveness of the product.
(3) Prior to filling, the final container shall be identified by
number so as to relate it to the donor.
(g) The final product. (1) The final product shall be inspected
immediately after separation of the plasma and shall not be issued for
transfusion if there is (i) any abnormality in color or physical
appearance, or (ii) any indication of contamination.
(2) With the exception of Platelet Rich Plasma and Liquid Plasma the
final product shall be inspected for evidence of thawing or breakage at
the time of issuance, however, the containers need not be stored in a
manner that shows evidence of thawing if records of continuous
monitoring of the storage temperature establish that the temperature
remained at -18 [deg]C or colder. If continuous monitoring of the
product is not available, the final product shall be stored in a manner
that will show evidence of thawing and shall not be issued if there is
any evidence of thawing.
(3) No preservative shall be added to the final product.
[42 FR 59878, Nov. 22, 1977, as amended at 43 FR 34460, Aug. 4 1978; 48
FR 13026, Mar. 29, 1983; 50 FR 4139, Jan. 29, 1985; 64 FR 45373, Aug.
19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001; 72 FR
45888, Aug. 16, 2007]
Subpart E [Reserved]
Subpart F_Cryoprecipitate
Sec. 640.50 Cryoprecipitated AHF.
(a) Proper name and definition. The proper name of this product
shall be Cryoprecipitated AHF. The product is defined as a preparation
of antihemophilic factor, which is obtained from a single unit of plasma
collected and processed in a closed system.
(b) Source. The source material for Cryoprecipitated AHF shall be
plasma which may be obtained by whole blood collection or by
plasmapheresis.
[42 FR 21774, Apr. 29, 1977; 48 FR 13026, Mar. 29, 1983; as amended at
50 FR 4139, Jan. 29, 1985]
Sec. 640.51 Suitability of donors.
(a) Whole blood donors shall meet the criteria for suitability
prescribed in Sec. 640.3.
(b) Plasmapheresis donors shall meet the criteria for suitability
prescribed in Sec. 640.63, excluding the phrase ``other than malaria''
in paragraph (c) (9) of that section. Informed consent shall be required
as prescribed in Sec. 640.61.
[42 FR 21774, Apr. 29, 1977, as amended at 64 FR 45373, Aug. 19, 1999;
73 FR 49942, Aug. 25, 2008]
Sec. 640.52 Collection of source material.
(a) Whole blood used as a source of Cryoprecipitated AHF shall be
collected as prescribed in Sec. 640.4. Whole blood from which both
Platelets and Cryoprecipitated AHF is derived shall be maintained as
required under Sec. 640.24 until the platelets are removed.
(b) If plasmapheresis is used, the procedure for collection shall be
as prescribed in Sec. Sec. 640.62, 640.64 (except that
[[Page 106]]
paragraph (c)(3) of that section shall not apply), and 640.65.
[42 FR 21774, Apr. 29, 1977, as amended by 50 FR 4139, Jan. 29, 1985; 64
FR 45373, Aug. 19, 1999]
Sec. 640.53 Testing the blood.
(a) Blood from which plasma is separated for the preparation of
Cryoprecipitated AHF shall be tested as prescribed in Sec. 610.40 of
this chapter and Sec. 640.5 (a), (b), and (c).
(b) The tests shall be performed on a sample of blood collected at
the time of collecting the source blood, and such sample container shall
be labeled with the donor's number before the container is filled.
(c) Manufacturers of Cryoprecipitated AHF obtained from plasma
collected by plasmapheresis shall have testing and record-keeping
responsibilities equivalent to those prescribed in Sec. Sec. 640.71 and
640.72.
[42 FR 21774, Apr. 29, 1977, as amended at 42 FR 37546, July 22, 1977;
42 FR 43063, Aug. 26, 1977; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan.
5, 1988; 66 FR 31165, June 11, 2001]
Sec. 640.54 Processing.
(a) Processing the plasma. (1) The plasma shall be separated from
the red blood cells by centrifugation to obtain essentially cell-free
plasma.
(2) The plasma shall be placed in a freezer within 8 hours after
blood collection or within the timeframe specified in the directions for
use for the blood collecting, processing, and storage system. A
combination of dry ice and organic solvent may be used for freezing:
Provided, That the procedure has been shown not to cause the solvent to
penetrate the container or leach plasticizer from the container into the
plasma.
(3) Immediately after separation and freezing of the plasma, the
plasma shall be stored and maintained at -18 [deg]C or colder until
thawing of the plasma for further processing to remove the
Cryoprecipitated AHF.
(b) Processing the final product. (1) The Cryoprecipitated AHF shall
be separated from the plasma by a procedure that has been shown to
produce an average of no less than 80 units of antihemophilic factor per
final container.
(2) No diluent shall be added to the product by the manufacturer
prior to freezing.
(3) The final container used for Cryoprecipitated AHF shall be
colorless and transparent to permit visual inspection of the contents;
any closure shall maintain a hermetic seal and prevent contamination of
the contents. The container material shall not interact with the
contents under customary conditions of storage and use in such a manner
as to have an adverse effect upon the safety, purity, potency and
effectiveness of the product. At the time of filling, the final
container shall be identified by a number so as to relate it to the
donor.
[42 FR 21774, Apr. 29, 1977, as amended at 47 FR 15330, Apr. 9, 1982; 50
FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1837, Jan. 10,
2001; 66 FR 40890, Aug. 6, 2001]
Sec. 640.55 U.S. Standard preparation.
A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may
be obtained from the Center for Biologics Evaluation and Research, (HFM-
407) (see mailing addresses in Sec. 600.2 of this chapter) for use in
the preparation of a working reference to be employed in a quality
control potency test of Cryoprecipitated AHF.
[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar.
24, 2005]
Sec. 640.56 Quality control test for potency.
(a) Quality control tests for potency of antihemophilic factor shall
be conducted each month on at least four representative containers of
Cryoprecipitated AHF.
(b) The results of each test are received by the establishment
licensed for Cryoprecipitated AHF within 30 days of the preparation of
the cryoprecipitated antihemophilic factor and are maintained at that
establishment so that they may be reviewed by an authorized
representative of the Food and Drug Administration.
(c) The quality control test for potency may be performed by a
clinical laboratory which meets the standards of the Clinical
Laboratories Improvement Amendments of 1988 (CLIA) (42
[[Page 107]]
U.S.C. 263a) and is qualified to perform potency tests for
antihemophilic factor. Such arrangements must be approved by the
Director, Center for Biologics Evaluation and Research, Food and Drug
Administration. Such testing shall not be considered as divided
manufacturing, as described in Sec. 610.63 of this chapter, provided
the following conditions are met:
(1) The establishment licensed for Cryoprecipitated AHF has obtained
a written agreement that the testing laboratory will permit an
authorized representative of the Food and Drug Administration to inspect
its testing procedures and facilities during reasonable business hours.
(2) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
(d) If the average potency level of antihemophilic factor in the
containers tested is less than 80 units of antihemophilic factor per
container, immediate corrective actions shall be taken and a record
maintained of such action.
[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45373, Aug.
19, 1999; 66 FR 1837, Jan. 10, 2001]
Subpart G_Source Plasma
Sec. 640.60 Source Plasma.
The proper name of the product shall be Source Plasma. The product
is defined as the fluid portion of human blood collected by
plasmapheresis and intended as source material for further manufacturing
use. The definition excludes single donor plasma products intended for
intravenous use.
[41 FR 10768, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985]
Sec. 640.61 Informed consent.
The written consent of a prospective donor shall be obtained after a
qualified licensed physician has explained the hazards of the procedure
to the prospective donor. The explanation shall include the risks of a
hemolytic transfusion reaction if he is given the cells of another
donor, and the hazards involved if he is hyperimmunized. The explanation
shall consist of such disclosure and be made in such a manner that
intelligent and informed consent be given and that a clear opportunity
to refuse is presented.
Sec. 640.62 Medical supervision.
A qualified licensed physician shall be on the premises when donor
suitability is being determined, immunizations are being made, whole
blood is being collected, and red blood cells are being returned to the
donor.
[66 FR 1837, Jan. 10, 2001]
Sec. 640.63 Suitability of donor.
(a) Method of determining. The suitability of a donor for Source
Plasma shall be determined by a qualified licensed physician or by
persons under his supervision and trained in determining donor
suitability. Such determination shall be made on the day of collection
from the donor by means of a medical history, tests, and such physical
examination as appears necessary to the qualified licensed physician.
(b) Initial medical examinations. (1) Each donor shall be examined
by a qualified licensed physician on the day of the first donation or no
more than 1 week before the first donation and at subsequent intervals
of no longer than 1 year.
(2)(i) A donor who is to be immunized for the production of high-
titer plasma shall be examined by a qualified licensed physician. The
medical examination shall be performed within no more than 1 week before
the first immunization injection. The medical examination for
plasmapheresis need not be repeated, if the first donation occurs within
3 weeks after the first injection.
(ii) A donor who is an active participant in a plasmapheresis
program, and has been examined in accordance with paragraph (b)(1) of
this section, need not be reexamined before immunization for the
production of high-titer plasma.
(3) Each donor shall be certified to be in good health by the
examining physician. The certification of good health shall be on a form
supplied by the licensed establishment and shall indicate that the
certification applies to the suitability of the individual to be a
[[Page 108]]
plasmapheresis donor and, when applicable, an immunized donor.
(c) Qualification of donor. Donors shall be in good health on the
day of donation, as indicated in part by:
(1) Normal temperature;
(2) Demonstration that systolic and diastolic blood pressures are
within normal limits, unless the examining physician is satisfied that
an individual with blood pressures outside these limits is an otherwise
qualified donor under the provisions of this section;
(3) A blood hemoglobin level of no less than 12.5 grams of
hemoglobin per 100 milliliters of blood or a hematocrit level of 38
percent;
(4) A normal pulse rate;
(5) A total serum or total plasma protein of no less than 6.0 grams
per 100 milliliters of blood;
(6) Weight, which shall be at least 110 pounds;
(7) Freedom from acute respiratory diseases;
(8) Freedom from any infectious skin disease at the site of
phlebotomy and from any such disease generalized to such an extent as to
create a risk of contamination of the plasma;
(9) Freedom from any disease, other than malaria, transmissible by
blood transfusion, insofar as can be determined by history and
examinations indicated in this section;
(10) Freedom of the arms and forearms from skin punctures or scars
indicative of addiction to self-injected narcotics;
(11) Freedom from a history of viral hepatitis after the 11th
birthday;
(12) Freedom from a history of close contact within 12 months of
donation with an individual having viral hepatitis;
(13) Freedom from a history of having received, within 12 months,
human blood or any derivative of human blood which the Food and Drug
Administration has advised the blood establishment is a possible source
of viral hepatitis, except for specific immunization performed in
accordance with Sec. 640.66.
(d) General. Any donor who, in the opinion of the interviewer,
appears to be under the influence of any drug, alcohol, or for any
reason does not appear to be providing reliable answers to medical
history questions, shall not be considered a suitable donor.
(e) Failure to return red blood cells. Any donor who has not had the
red blood cells returned from a unit of blood collected during a
plasmapheresis procedure or who has been a donor of a unit of whole
blood shall not be subjected to plasmapheresis for a period of 8 weeks,
unless:
(1) The donor has been examined by a qualified licensed physician
and certified by the physician to be acceptable for further
plasmapheresis before expiration of the 8-week period;
(2) The donor possesses an antibody that is (i) transitory, (ii) of
a highly unusual or infrequent specificity, or (iii) of an unusually
high titer; and
(3) The special characteristics of the antibody and the need for
plasmapheresing the donor are documented.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10768, Mar. 12, 1976;
43 FR 9805, Mar. 10, 1978; 43 FR 12311, Mar. 24, 1978; 46 FR 57480, Nov.
24, 1981; 50 FR 4140, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 66 FR
1837, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001]
Sec. 640.64 Collection of blood for Source Plasma.
(a) Supervision. All blood for the collection of Source Plasma shall
be drawn from the donor by a qualified licensed physician or by persons
under his supervision trained in the procedure.
(b) Blood containers. Blood containers and donor sets must be
pyrogen-free, sterile, and identified by lot number.
(c) The anticoagulant solution. The anticoagulant solution must be
sterile and pyrogen-free. Anticoagulant solutions must be compounded and
used according to a formula that has been approved for the applicant by
the Director, Center for Biologics Evaluation and Research.
(d) Donor identification. Each unit of blood and plasma shall be so
marked or identified by number or other symbol so as to relate it
directly to the donor.
(e) Prevention of contamination of the blood and plasma. The skin of
the donor at the site of phlebotomy shall be prepared thoroughly and
carefully by a method that gives maximum assurance of a sterile
container of blood. The
[[Page 109]]
blood shall be collected, the plasma separated, and the cells returned
to the donor by aseptic methods in a sterile system which may be closed,
or may be vented if the vent protects the blood cells and plasma against
contamination.
[38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr. 16, 1974, as amended at
41 FR 10768, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan.
29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR
16685, Apr. 6, 1998; 64 FR 56453, Oct. 20, 1999; 72 FR 45888, Aug. 16,
2007]
Sec. 640.65 Plasmapheresis.
(a) Procedure-general. The plasmapheresis procedure is a procedure
in which, during a single visit to the establishment, blood is removed
from a donor, the plasma separated from the formed elements, and at
least the red blood cells returned to the donor. This procedure shall be
described in detail in the biologics license application.
(b) Procedures-specific requirements. The plasmapheresis procedure
shall meet the following requirements:
(1)(i) A sample of blood shall be drawn from each donor on the day
of the first medical examination or plasmapheresis, whichever comes
first and at least every 4 months thereafter by a qualified licensed
physician or by persons under his supervision and trained in such
procedure. A serologic test for syphilis, a total plasma or serum
protein determination, and a plasma or serum protein electrophoresis or
quantitative immuno-diffusion test or an equivalent test to determine
immunoglobulin composition of the plasma or serum shall be performed on
the sample.
(ii) A repeat donor who does not return for plasmapheresis at the
time the 4-month sample is due to be collected may be plasmapheresed on
the day he appears: Provided, That no longer than 6 months has elapsed
since the last sample was collected, and the physician on the premises
approves the plasmapheresis procedure and so indicates by signing the
donor's record before such procedure is performed. The sample for the 4-
month tests shall be collected on the day of the donor's return.
(iii) A repeat donor from whom the plasmapheresis center is unable
to obtain a sample for testing as prescribed in paragraph (b)(1)(i) of
this section for a total period exceeding 6 months shall be processed as
a new donor.
(2)(i) The accumulated laboratory data, including tracings, if any,
of the plasma or serum protein electrophoresis pattern, the calculated
values of each component, and the collection records shall be reviewed
by a qualified licensed physician within 21 days after the sample is
drawn to determine whether or not the donor may continue in the program.
The review shall be signed by the reviewing physician. If the protein
composition is not within normal limits established by the testing
laboratory, or if the total protein is less than 6.0 grams per 100
milliliters of samples, the donor shall be removed from the program
until these values return to normal.
(ii) A donor with a reactive serologic test for syphilis shall not
be plasmapheresed again until the donor's serum is tested and found to
be nonreactive to a serologic test for syphilis, except as provided in
paragraph (b)(2) (iii) and (iv) of this section.
(iii) A donor whose serum is determined to have a biologic false-
positive reaction to a serologic test for syphilis may be
plasmapheresed: Provided, That the donor's file identifies the serologic
test for syphilis and results used to confirm the biologic false-
positive reaction and indicates that the physician on the premises has
determined the false-positive reaction is not the result of an
underlying disorder that would disqualify the donor from participation
in the plasmapheresis program. If the serologic test for syphilis is
performed at a facility other than the plasmapheresis center, all
applicable provisions of Sec. 640.71 shall be met.
(iv) A donor with a reactive serologic test for syphilis may be
plasmapheresed only to obtain plasma to be used for further
manufacturing into control serum for the serologic test for syphilis:
Provided, That the physician on the premises approves the donation, the
donor's file contains a signed statement from a physician or clinic
establishing that treatment for syphilis has been initiated and that
[[Page 110]]
continuance in the plasmapheresis program will not interfere with or
jeopardize the treatment of the syphilitic donor.
(3) A donor identification system shall be established that
positively identifies each donor and relates such donor directly to his
blood and its components as well as to his accumulated records and
laboratory data. Such system shall include either a photograph of each
donor which shall be used on each visit to confirm the donor's identity,
or some other method that provides equal or greater assurance of
positively identifying the donor.
(4) The amount of whole blood, not including anticoagulant, removed
from a donor during a manual plasmapheresis procedure or in any 2-day
period shall not exceed 1,000 milliliters unless the donor's weight is
175 pounds or greater, in which case the amount of whole blood, not
including anticoagulant, removed from the donor during a manual
plasmapheresis procedure or in any 2-day period shall not exceed 1,200
milliliters.
(5) The amount of whole blood, not including anticoagulant, removed
from a donor during a manual plasmapheresis procedure within a 7-day
period shall not exceed 2,000 milliliters unless the donor's weight is
175 pounds or greater, in which case the amount of whole blood, not
including anticoagulant, removed from a donor during a manual
plasmapheresis procedure within a 7-day period shall not exceed 2,400
milliliters.
(6) No more than 500 milliliters of whole blood shall be removed
from a donor at one time, unless the donor's weight is 175 pounds or
greater, in which case no more than 600 milliliters of whole blood shall
be removed from the donor at one time.
(7) The plasma shall be separated from the red blood cells
immediately after blood collection. The maximum feasible volume of red
blood cells shall be returned to the donor before another unit is
collected.
(8) The volume of plasma collected during an automated
plasmapheresis collection procedure shall be consistent with the volumes
specifically approved by the Director, Center for Biologics Evaluation
and Research, and collection shall not occur less than 2 days apart or
more frequently than twice in a 7-day period.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976;
64 FR 45373, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999]
Sec. 640.66 Immunization of donors.
If specific immunization of a donor is to be performed, the
selection and scheduling of the injection of the antigen, and the
evaluation of each donor's clinical response, shall be by a qualified
licensed physician or physicians. The administration of the antigen may
be performed by a licensed physician or a trained person under his
supervision. Any material used for immunization shall be either a
product licensed under section 351 of the Public Health Service Act for
such purpose or one specifically approved by the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration.
Immunization procedures shall be on file at each plasmapheresis center
where immunizations are performed.
[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 640.67 Laboratory tests.
Each unit of Source Plasma shall be tested for evidence of infection
due to communicable disease agents as required under Sec. 610.40 of
this chapter.
[66 FR 31165, June 11, 2001]
Sec. 640.68 Processing.
(a) Sterile system. All administration and transfer sets inserted
into blood containers used for processing Source Plasma intended for
manufacturing into injectable or noninjectable products and all interior
surfaces of plasma containers used for processing Source Plasma intended
for manufacturing into injectable products shall be sterile, pyrogen-
free, nontoxic, and compatible with the contents under normal conditions
of use. Only Sodium Chloride Injection USP shall be used as a red blood
cell diluent. If the method of separation of the plasma intended for
injectable products involves a system in which an airway must be
inserted into the plasma container, the airway shall be sterile and
constructed so as to
[[Page 111]]
exclude microorganisms and maintain a sterile system.
(b) Final containers. Final containers used for Source Plasma,
whether integrally attached or separated from the original blood
container, shall not be entered prior to issuance for any purpose except
for filling with the plasma. Such containers shall be uncolored and
hermetically sealed, and shall permit clear visibility of the contents.
Final containers and their components shall not interact with the plasma
contents under conditions of storage and use so as to alter the safety,
quality, purity, or potency of the plasma and shall provide adequate
protection against external factors that may cause deterioration or
contamination. Prior to filling, the final container shall be marked or
identified by number or other symbol which will relate it directly to
the donor.
(c) Preservative. Source Plasma shall not contain a preservative.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976;
50 FR 4140, Jan. 29, 1985]
Sec. 640.69 General requirements.
(a) Pooling. Two units of Source Plasma from the same donor may be
pooled if such units are collected during one plasmapheresis procedure:
Provided, That the pooling is done by a procedure that does not
introduce a risk of contamination of the red blood cells and, for plasma
intended for injectable products, gives maximum assurance of a sterile
container of plasma.
(1) The pooling of plasma from two or more donors is not permitted
in the manufacture of Source Plasma intended for manufacturing into
injectable products.
(2) The pooling of plasma from two or more donors by the
manufacturer of Source Plasma intended for manufacturing into
noninjectable products is permitted: Provided, That the plasma from two
or more donors is pooled after the plasma has been removed from the red
blood cells, and after the red blood cell containers are sealed.
(b) Storage. Immediately after filling, plasma intended for
manufacturing into injectable products shall be stored at a temperature
not warmer than -20 [deg]C, except for plasma collected as provided in
Sec. 640.74. Plasma intended for manufacturing into noninjectable
products may be stored at temperatures appropriate for the intended use
of the final product, provided these temperatures are included in the
Source Plasma license application.
(c) Inspection. Source Plasma intended for manufacturing into
injectable products shall be inspected for evidence of thawing at the
time of issuance, except that inspection of individual plasma containers
need not be made if the records of continuous monitoring of the storage
temperature establish that the temperature remained at -20 [deg]C or
colder. If there is evidence that the storage temperature has not been
maintained at -20 [deg]C or colder, the plasma may be relabeled and
issued as provided in Sec. 640.76(a).
(d) Samples. If samples are provided, they shall meet the following
standards:
(1) Prior to filling, all samples shall be marked or identified so
as to relate them directly to the donor of that unit of plasma.
(2) All samples shall be filled at the time the final product is
prepared by the person who prepares the final product.
(3) All samples shall be representative of the contents of the final
product or be collected from the donor at the time of filling the
collection container.
(4) All samples shall be collected in a manner that does not
contaminate the contents of the final container.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976;
41 FR 14367, Apr. 5, 1976; 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr.
6, 1998; 64 FR 45374, Aug. 19, 1999]
Sec. 640.70 Labeling.
(a) In addition to the labeling requirements of Sec. 610.62 of this
chapter, and in lieu of the requirements in Sec. Sec. 606.121, 610.60,
and 610.61 of this chapter, the following information shall appear on
the label affixed to each container of Source Plasma:
(1) The proper name of the product.
(2) The statement ``Caution: For Manufacturing Use Only'' for
products intended for further manufacturing into injectable products, or
the statement, ``Caution: For Use In Manufacturing Noninjectable
Products Only'',
[[Page 112]]
for products intended for further manufacturing into noninjectable
products. The statement shall follow the proper name in the same size
and type of print as the proper name. If the Source Plasma has a
reactive screening test for evidence of infection due to a communicable
disease agent(s) under Sec. 610.40 of this chapter, or is collected
from a donor with a previous record of a reactive screening test for
evidence of infection due to a communicable disease agent(s) under Sec.
610.40 of this chapter, the Source Plasma must be labeled under Sec.
610.40(h)(2)(ii)(E) of this chapter.
(3) The statement ``Store at -20 [deg]C or colder'': Provided, That
where plasma is intended for manufacturing into noninjectable products,
this statement may be omitted if replaced by a statement of the
temperature appropriate for the final product to be prepared from the
plasma.
(4) The total volume or weight of plasma and total quantity and type
of anticoagulant used.
(5) The donor number or individual bleed number, or both. If plasma
is pooled from two or more donors, either all donor numbers, all bleed
numbers, or a pool number that is traceable to each individual unit
comprising the pool.
(6) The expiration date of the plasma. If plasma intended for
manufacturing into noninjectable products is pooled from two or more
donors the expiration date is determined from the collection date of the
oldest unit in the pool, and the pooling records shall show the
collection date for each unit constituting the pool.
(7) A statement as to whether the plasma was collected from normal
donors or from immunized donors. In the case of immunized donors, the
label shall state the immunizing antigen.
(8) The test for hepatitis B surface antigen used for the results,
or the statement ``Nonreactive for HBs Ag by FDA required
test''.
(9) When plasma collected from a donor is reactive for the serologic
test for syphilis, a statement that the plasma is reactive and must be
used only for the manufacturing of positive control reagents for the
serologic test for syphilis.
(10) Name, address, and license number of the manufacturer.
(11) The statement ``Negative by a test for antibody to HIV'', or
equivalent statement.
(b) Source Plasma diverted for Source Plasma Salvaged shall be
relabeled ``Source Plasma Salvaged'' as prescribed in Sec. 640.76.
Immediately following the proper name of the product, the labeling shall
conspicuously state as applicable, ``STORAGE TEMPERATURE EXCEEDED -20
[deg]C'' or ``SHIPPING TEMPERATURE EXCEEDED -5 [deg]C''.
[41 FR 10770, Mar. 12, 1976, as amended at 41 FR 27034, July 1, 1976; 41
FR 35062, Aug. 19, 1976; 47 FR 30969, July 16, 1982; 50 FR 4140, Jan.
29, 1985; 50 FR 35471, Aug. 30, 1985; 53 FR 117, Jan. 5, 1988; 63 FR
16685, Apr. 6, 1998; 66 FR 31165, June 11, 2001]
Sec. 640.71 Manufacturing responsibility.
(a) All steps in the manufacturing of Source Plasma, including donor
examination, blood collection, plasmapheresis, laboratory testing,
labeling, storage, and issuing shall be performed by personnel of the
establishment licensed to manufacture Source Plasma, except that the
following tests may be performed by personnel of an establishment
licensed for blood and blood derivatives under section 351(a) of the
Public Health Service Act, or by a clinical laboratory that meets the
standards of the Clinical Laboratories Improvement Amendments of 1988
(CLIA) (42 U.S.C. 263a): Provided, The establishment or clinical
laboratory is qualified to perform the assigned test(s).
(1) The test for hepatitis B surface antigen.
(2) The total plasma or serum protein and the quantitative test for
plasma or serum proteins or for immunoglobulins.
(3) The serologic test for syphilis.
(4) A test for antibody to HIV.
(b) Such testing shall not be considered divided manufacturing,
which requires two biologics licenses for Source Plasma: Provided, That
(1) The results of such tests are maintained by the licensed
manufacturer of the Source Plasma whereby such results may be reviewed
by a licensed physician as required in Sec. 640.65(b)(2) of
[[Page 113]]
this chapter and by an authorized representative of the Food and Drug
Administration.
(2) The Source Plasma manufacturer has obtained a written agreement
that the testing laboratory will permit authorized representatives of
the Food and Drug Administration to inspect its testing procedures and
facilities during reasonable business hours.
(3) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. 26,
1990; 64 FR 45374, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 66 FR
1837, Jan. 10, 2001]
Sec. 640.72 Records.
(a) In addition to the recordkeeping requirements of this
subchapter, the following records shall be maintained:
(1) Documentation shall be available to ensure that the shipping
temperature requirements of Sec. 600.15 of this title and of Sec.
640.74(b)(2) are being met for Source Plasma intended for manufacture
into injectable products.
(2) For each donor, a separate and complete record of all initial
and periodic examinations, tests, laboratory data, interviews, etc.,
undertaken pursuant to Sec. Sec. 640.63, 640.65, 640.66, and 640.67,
except that negative test results for hepatitis B surface antigen,
negative test results for antibody to HIV, and the volume or weight of
plasma withdrawn from a donor need not be kept on the individual donor
record: Provided, That such information is maintained on the premises of
the plasmapheresis center where the donor's plasma has been collected.
(3) The original or a clear copy of the donor's written consent for
participation in the plasmapheresis program or for immunization.
(4) The certification of the donor's good health as prescribed in
Sec. 640.63(b)(3).
(5) If plasma that is reactive to a serologic test for syphilis is
issued as prescribed in Sec. 640.65(b)(2)(iv), the distribution records
shall indicate by number those units that are reactive.
(b) Each donor record must be directly cross-referenced to the
unit(s) of Source Plasma associated with the donor.
(c) If a repeat donor is rejected or a donor's plasma is found
unsuitable, the donor's record shall contain a full explanation for the
rejection.
(d) If a donor has a reaction while on the plasmapheresis premises,
or a donor reaction is reported to the center after the donor has left
the premises, the donor's record shall contain a full explanation of the
reaction, including the measures taken to assist the donor and the
outcome of the incident.
[41 FR 10770, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985; 53
FR 117, Jan. 5, 1988; 64 FR 45374, Aug. 19, 1999; 67 FR 9587, Mar. 4,
2002]
Sec. 640.73 Reporting of fatal donor reactions.
If a donor has a fatal reaction which, in any way, may be associated
with plasmapheresis the Director of the Center for Biologics Evaluation
and Research shall be notified by telephone as soon as possible. If the
facility is located outside of the continental United States,
notification by cable or telegram shall be acceptable.
[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 640.74 Modification of Source Plasma.
(a) Upon approval by the Director, Center for Biologics Evaluation
and Research, Food and Drug Administration, of a supplement to the
biologics license application for Source Plasma, a manufacturer may
prepare Source Plasma as a liquid product for a licensed blood
derivative manufacturer who has indicated a need for a liquid product.
(b) Source Plasma Liquid shall meet all standards of the frozen
Source Plasma except:
(1) Source Plasma Liquid shall be stored in nonleachable containers
so that the containers and their components will not interact with the
plasma contents under conditions of storage and use so as to alter the
safety, quality, purity, or potency of the plasma and shall provide
adequate protection
[[Page 114]]
against external factors that may cause deterioration or contamination.
(2) Source Plasma Liquid shall be shipped, stored and labeled for
storage at a temperature of 10 [deg]C or colder. An exception to the
shipping or storage temperature shall be approved by the Director,
Center for Biologics Evaluation and Research, Food and Drug
Administration, based upon his receipt of substantial evidence to
support another temperature. Such evidence may be submitted by either
the licensed manufacturer of the Source Plasma Liquid or the
manufacturer of the final blood derivative product who has requested the
Source Plasma Liquid.
(3) The label for the Source Plasma Liquid shall be easily
distinguished from that of the frozen product. Color coding shall not be
used for this purpose.
(4) The label affixed to each container of Source Plasma Liquid
shall contain, in addition to the information required by Sec.
640.70(a) but excluding Sec. 640.70(a)(3), the name of the manufacturer
of the final blood derivative product for whom it was prepared.
(5) Source Plasma Liquid shall be inspected immediately prior to
issuance. If the color or physical appearance is abnormal, or there is
any indication or suspicion of microbial contamination, the unit of
Source Plasma Liquid shall not be issued.
[38 FR 32089, Nov. 20, 1973. Redesignated and amended at 41 FR 10770,
Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55
FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr.
6, 1998; 64 FR 56454, Oct. 20, 1999]
Sec. 640.76 Products stored or shipped at unacceptable temperatures.
(a) Storage temperature. (1) Except as provided in paragraph (a)(2)
of this section, Source Plasma intended for manufacture into injectable
products that is inadvertently exposed (i.e., an unforeseen occurrence
in spite of compliance with good manufacturing practice) to a storage
temperature warmer than -20 [deg]C and colder than +10 [deg]C may be
issued only if labeled as ``Source Plasma Salvaged.'' The label shall be
revised before issuance, and appropriate records shall be maintained
identifying the units involved, describing their disposition, and
explaining fully the conditions that caused the inadvertent temperature
exposure.
(2) Source Plasma intended for manufacture into injectable products
that is exposed inadvertently (i.e., an unforeseen occurrence in spite
of compliance with good manufacturing practice) to one episode of
storage temperature fluctuation that is warmer than -20 [deg]C and
colder than -5 [deg]C for not more than 72 hours is exempt from the
labeling requirements of paragraph (a)(1) of this section, provided that
the plasma has been and remains frozen solid. Appropriate records shall
be maintained identifying the units involved, describing their
disposition, explaining fully the conditions that caused the inadvertent
temperature exposure, and documenting that the episode of temperature
elevation did not exceed 72 hours, that the temperature did not rise to
warmer than -5 [deg]C in storage, and that the plasma remained frozen
solid throughout the period of elevated temperature. When requested,
copies of the records shall be provided to the plasma derivative
manufacturer.
(b) Shipping temperature. If Source Plasma for manufacture into
injectable products is exposed inadvertently (i.e., an unforeseen
occurrence in spite of compliance with good manufacturing practice) to a
shipping temperature warmer than -5 [deg]C and colder than +10 [deg]C,
the plasma derivative manufacturer shall label it ``Source Plasma
Salvaged.'' Appropriate records shall be maintained identifying the
units involved, describing their disposition, and explaining fully the
conditions that caused the inadvertent temperature exposure.
(c) Relabeling. If Source Plasma is required to be relabeled as
``Source Plasma Salvaged'' under paragraph (a)(1) or (b) of this
section, the person responsible for the relabeling shall cover the
original label with either (1) a complete new label containing the
appropriate information or (2) a partial label affixed to the original
label and containing the appropriate new information, which covers the
incorrect information regarding storage temperature.
[45 FR 80501, Dec. 5, 1980, as amended at 50 FR 4140, Jan. 29, 1985]
[[Page 115]]
Subpart H_Albumin (Human)
Sec. 640.80 Albumin (Human).
(a) Proper name and definition. The proper name of the product shall
be Albumin (Human). The product is defined as a sterile solution of the
albumin derived from human plasma.
(b) Source material. The source material of Albumin (Human) shall be
plasma recovered from Whole Blood prepared as prescribed in Sec. Sec.
640.1 through 640.5, or Source Plasma prepared as prescribed in
Sec. Sec. 640.60 through 640.76.
(c) Additives in source material. Source material shall not contain
an additive unless it is shown that the processing method yields a final
product free of the additive to such extent that the continued safety,
purity, potency, and effectiveness of the final product will not be
adversely affected.
[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64
FR 26286, May 14, 1999]
Sec. 640.81 Processing.
(a) Date of manufacture. The date of manufacture shall be the date
of final sterile filtration of a uniform pool of bulk solution.
(b) Processing method. The processing method shall not affect the
integrity of the product, and shall have been shown to yield
consistently a product which is safe for intravenous injection.
(c) Microbial contamination. All processing steps shall be conducted
in a manner to minimize the risk of contamination from microorganisms,
pyrogens, or other impurities. Preservatives to inhibit growth of
microorganisms shall not be used during processing.
(d) Storage of bulk fraction. Bulk concentrate to be held more than
1 week prior to further processing shall be stored in clearly identified
closed vessels at a temperature of -5 [deg]C or colder. Any other bulk
form of the product, exclusive of the sterile bulk solution, to be held
more than 1 week prior to further processing shall be stored in clearly
identified closed vessels at a temperature of 5 [deg]C or colder. Any
bulk fraction to be held one week or less prior to further processing
shall be stored in clearly identified closed vessels at a temperature of
5 [deg]C or colder.
(e) Heat treatment. Heating of the final containers of Albumin
(Human) shall begin within 24 hours after completion of filling. Heat
treatment shall be conducted so that the solution is heated continuously
for not less than 10, or more than 11 hours, at an attained temperature
of 600.5 [deg]C.
(f) Stabilizer. Either 0.080.016 millimole
sodium caprylate, or 0.080.016 millimole sodium
acetyltryptophanate and 0.080.016 millimole sodium
caprylate per gram of protein shall be present as a stabilizer(s).
Calculations of the stabilizer concentration may employ the labeled
value for the protein concentration of the product as referred to in
Sec. 640.84(d).
(g) Incubation. All final containers of Albumin (Human) shall be
incubated at 20 to 35 [deg]C for at least 14 days following the heat
treatment prescribed in paragraph (e) of this section. At the end of
this incubation period, each final container shall be examined and all
containers showing any indication of turbidity or microbial
contamination shall not be issued. The contents of turbid final
containers shall be examined microscopically and tested for sterility.
If growth occurs, organisms shall be identified as to genus, and the
material from such containers shall not be used for further
manufacturing.
[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64
FR 26286, May 14, 1999; 65 FR 13679, Mar. 14, 2000; 65 FR 52018, Aug.
28, 2000]
Sec. 640.82 Tests on final product.
Tests shall be performed on the final product to determine that it
meets the following standards:
(a) Protein concentration. Final product shall conform to one of the
following concentrations: 4.0 0.25 percent; 5.0
0.30 percent; 20.0 1.2
percent; and 25.0 1.5 percent solution of protein.
(b) Protein composition. At least 96 percent of the total protein in
the final product shall be albumin, as determined by a method that has
been approved for each manufacturer by the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration.
(c) pH. The pH shall be 6.9 0.5 when measured
in a solution of the final
[[Page 116]]
product diluted to a concentration of 1 percent protein with 0.15 molar
sodium chloride.
(d) Sodium concentration. The sodium concentration of the final
product shall be 130 to 160 milliequivalents per liter.
(e) Potassium concentration. The potassium concentration of the
final product shall not exceed 2 milliequivalents per liter.
(f) Heat stability. A final container sample of Albumin (Human)
shall remain unchanged, as determined by visual inspection, after
heating at 57 [deg]C for 50 hours, when compared to its control
consisting of a sample, from the same lot, which has not undergone this
heating.
[42 FR 27582, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 26286, May 14,
1999]
Sec. 640.83 General requirements.
(a) Preservative. The final product shall not contain a
preservative.
(b) Storage of bulk solution. After all processing steps have been
completed, the sterile bulk solution shall be stored in a manner that
will ensure the continued sterility of the product, and at a temperature
that shall not exceed the recommended storage temperature of the final
product prescribed in Sec. 610.53 of this chapter.
[42 FR 27582, May 31, 1977]
Sec. 640.84 Labeling.
In addition to the labeling requirements of Sec. Sec. 610.60,
610.61, and 610.62 of this chapter, the container and package labels
shall contain the following information:
(a) The osmotic equivalent in terms of plasma, and the sodium
concentration in terms of a value or a range in milliequivalents per
liter;
(b) The cautionary statement placed in a prominent position on the
label, ``Do Not Use if Turbid. Do Not Begin Administration More Than 4
Hours After the Container Has Been Entered.'';
(c) The need for additional fluids when 20 percent or 25 percent
albumin is administered to a patient with marked dehydration;
(d) The protein concentration, expressed as a 4 percent, 5 percent,
20 percent, or 25 percent solution.
[42 FR 27582, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984; 64
FR 26286, May 14, 1999]
Subpart I_Plasma Protein Fraction (Human)
Source: 42 FR 27583, May 31, 1977, unless otherwise noted.
Sec. 640.90 Plasma Protein Fraction (Human).
(a) Proper name and definition. The proper name of the product shall
be Plasma Protein Fraction (Human). The product is defined as a sterile
solution of protein composed of albumin and globulin, derived from human
plasma.
(b) Source material. The source material of Plasma Protein Fraction
(Human) shall be plasma recovered from Whole Blood prepared as
prescribed in Sec. Sec. 640.1 through 640.5, or Source Plasma prepared
as prescribed in Sec. Sec. 640.60 through 640.76.
(c) Additives in source material. Source material shall not contain
an additive unless it is shown that the processing method yields a final
product free of the additive to such extent that the continued safety,
purity, potency, and effectiveness of the final product will not be
adversely affected.
[42 FR 27583, May 31, 1977, as amended at 64 FR 26286, May 14, 1999]
Sec. 640.91 Processing.
(a) Date of manufacture. The date of manufacture shall be the date
of final sterile filtration of a uniform pool of bulk solution.
(b) Processing method. The processing method shall not affect the
integrity of the product, and shall have been shown to yield
consistently a product which:
(1) After the heating prescribed in paragraph (e) of this section
does not show an increase in the components with electrophoretic
mobility similar to that of alpha globulin that amounts to more than 5
percent of the total protein.
(2) Contains less than 5 percent protein with a sedimentation
coefficient greater than 7.0 S.
[[Page 117]]
(3) Is safe for intravenous injection.
(c) Microbial contamination. All processing steps shall be conducted
in a manner to minimize the risk of contamination from microorganisms,
pyrogens, or other impurities. Preservatives to inhibit growth of
microorganisms shall not be used during processing.
(d) Storage of bulk fraction. Bulk concentrate to be held more than
1 week prior to further processing shall be stored in clearly identified
closed vessels at a temperature of -5 [deg]C or colder. Any other bulk
form of the product (exclusive of the sterile bulk solution) to be held
more than 1 week prior to further processing, shall be stored in clearly
identified closed vessels at a temperature of 5 [deg]C or colder. Any
bulk fraction to be held one week or less prior to further processing
shall be stored in clearly identified closed vessels at a temperature of
5 [deg]C or colder.
(e) Heat treatment. Heating of the final containers of Plasma
Protein Fraction (Human) shall begin within 24 hours after completion of
filling. Heat treatment shall be conducted so that the solution is
heated continuously for not less than 10 or more than 11 hours at an
attained temperature of 60